Severe Toxic Effects Research Articles

Impacts of micro/nano plastics on the ecotoxicological effects of antibiotics in agricultural soil: A comprehensive study based on meta-analysis and machine learning prediction

Micro/nano plastics (M/NPs) and antibiotics, as widely coexisting pollutants in environment, pose serious threats to soil ecosystem. The purpose of this study was to systematically evaluate the ecological effects of the co-exposure of M/NPs and antibiotics on soil organisms through the meta-analysis and machine learning prediction. Totally, 1002 data set from 38 articles were studied. The co-exposure of M/NPs significantly promoted the abundance (62.68 %) and migration level (55.22 %) of antibiotic contamination in soil, and caused serious biotoxicity to plants (−12.31 %), animals (−12.03 %), and microorganisms (35.07 %). Using 10 variables, such as risk response categories, basic physicochemical properties, exposure objects, and exposure time of M/NPs, as data sources, Random Forests (RF) and eXtreme Gradient Boosting (XGBoost) models were developed to predict the impacts of M/NPs on the ecotoxicological effects of antibiotics in agricultural soil. The effective R2 values (0.58 and 0.60, respectively) indicated that both models can be used to predict the future ecological risk of M/NPs and antibiotics coexistence in soil. Particle size (13.54 %), concentration (5.02 %), and type (11.18 %) of M/NPs were the key characteristic parameters that affected the prediction results. The findings of this study indicate that the co-exposure of M/NPs and antibiotics in soil not only exacerbates antibiotic contamination levels but also causes severe toxic effects to soil organism. Furthermore, this study provides an effective approach for ecological risk assessment of the coexistence of M/NPs and antibiotics in environment.

Balancing Tumor Immunotherapy and Immune-Related Adverse Events: Unveiling the Key Regulators.

Tumor immunotherapy has emerged as a promising approach in cancer treatment in recent years, offering vast potential. This method primarily involves targeting and inhibiting the suppressive checkpoints present in different immune cells to enhance their activation, ultimately leading to tumor regression. However, tumor cells exploit the surrounding immune cells and tissues to establish a tumor microenvironment (TME) that supports their survival and growth. Within the TME, the efficacy of effector immune cells is compromised, as tumor cells exploit inhibitory immune cells to suppress their function. Furthermore, certain immune cells can be co-opted by tumor cells to facilitate tumor growth. While significantly enhancing the body's tumor immunity can lead to tumor regression, it can also result in severe toxic side effects and an inflammatory factor storm. As a consequence, patients often discontinue treatment due to immune-related adverse events (irAEs) or, in extreme cases, succumb to toxic side effects before experiencing tumor regression. In this analysis, we examined several remission regimens for irAEs, each with its own drawbacks, including toxic side effects or suppression of tumor immunotherapy, which is undesirable. A recent research study, specifically aimed at downregulating intestinal epithelial barrier permeability, has shown promising results in reducing the severity of inflammatory bowel disease (IBD) while preserving immune function. This approach effectively reduces the severity of IBD without compromising the levels of TNF-α and IFN-γ, which are crucial for maintaining the efficacy of tumor immunotherapy. Based on the substantial similarities between IBD and ICI colitis (combo immune checkpoint inhibitors-induced colitis), this review proposes that targeting epithelial cells represents a crucial research direction for mitigating irAEs in the future.

A comparative study on the toxic effects of lead pollution and nanoplastic-lead mixed pollution on red drum and their detoxification strategies

Nanoplastics and heavy metals pose various adverse effects on marine organisms. However, the combined toxicity of nanoplastics and lead pollution to marine fish is not fully understood. This study investigates the toxic effects and detoxification strategies of lead pollution (p07) compared to nanoplastic-lead mixed pollution (m07) in red drum during exposure and recovery phases. Under m07 pollution, the maximum lead content in muscle was 22.61 mg/kg, which was significantly higher than the 15.82 mg/kg observed under p07 pollution. This finding demonstrated that nanoplastics significantly enhance lead accumulation, leading to more severe toxic effects on red drum. Histological analyses revealed that lipid droplets in the liver and epithelial lifting in the gills were the primary lesion types. During the exposure periods, red drum primarily detoxified lead through cellular renewal and the removal of damaged proteins under p07 pollution. Conversely, under m07 pollution, detoxification relied on cellular senescence, apoptosis, endocytosis, and the removal of damaged proteins. In the recovery phases, red drum predominantly recovered through cell proliferation and antioxidant responses under p07 pollution. Under m07 pollution, the focus shifted to functional protein synthesis, apoptosis, endocytosis, and lipid metabolism. This study offers valuable insights into the monitoring and management of combined environmental pollution.

Encapsulation of Inositol Hexakisphosphate with Chitosan via Gelation to Facilitate Cellular Delivery and Programmed Cell Death in Human Breast Cancer Cells.

Inositol hexakisphosphate (InsP6) is the most abundant inositol polyphosphate both in plant and animal cells. Exogenous InsP6 is known to inhibit cell proliferation and induce apoptosis in cancerous cells. However, cellular entry of exogenous InsP6 is hindered due to the presence of highly negative charge on this molecule. Therefore, to enhance the cellular delivery of InsP6 in cancerous cells, InsP6 was encapsulated by chitosan (CS), a natural polysaccharide, via the ionic gelation method. Our hypothesis is that encapsulated InsP6 will enter the cell more efficiently to trigger its apoptotic effects. The incorporation of InsP6 into CS was optimized by varying the ratios of the two and confirmed by InsP6 analysis via polyacrylamide gel electrophoresis (PAGE) and atomic absorption spectrophotometry (AAS). The complex was further characterized by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR) for physicochemical changes. The data indicated morphological changes and changes in the spectral properties of the complex upon encapsulation. The encapsulated InsP6 enters human breast cancer MCF-7 cells more efficiently than free InsP6 and triggers apoptosis via a mechanism involving the production of reactive oxygen species (ROS). This work has potential for developing cancer therapeutic applications utilizing natural compounds that are likely to overcome the severe toxic effects associated with synthetic chemotherapeutic drugs.

Liver-targeting chimeras as a potential modality for the treatment of liver diseases

Liver diseases pose significant challenges to global public health. In the realm of drug discovery and development, overcoming ‘on-target off-tissue’ effects remains a substantial barrier for various diseases. In this study, we have pioneered a Liver-Targeting Chimera (LIVTAC) approach using a proteolysis-targeting chimera (PROTAC) molecule coupled to the liver-specific asialoglycoprotein receptor (ASGPR) through an innovative linker attachment strategy for the precise induction of target protein degradation within the liver. As a proof-of-concept study, we designed XZ1606, a mammalian bromodomain and extra-terminal domain (BET)-targeting LIVTAC agent, which not only demonstrated enduring tumor suppression (over 2 months) in combination with sorafenib but also an improved safety profile, notably ameliorating the incidence of thrombocytopenia, a common and severe on-target dose-limiting toxic effect associated with conventional BET inhibitors. These encouraging results highlight the potential of LIVTAC as a versatile platform for addressing a broad spectrum of liver diseases.

Divine noni's protective impact on Swiss albino mice's short-term memory impairment caused by cyclophosphamide: A behavioral and biochemical approach

Cyclophosphamide (CYL) is a first-line cancer chemotherapeutic agent widely used for the treatment of cancer that has severe toxic effects. The primary mechanism by which CYL induces toxicity through free radical generation. Morinda citrifolia (Noni) fruit juice is an herbal remedy documented to have antioxidant properties. The aim of the current study was to investigate the protective effect of noni against CYL-induced memory impairment in Swiss albino mice. Treatment schedule: Group 1: Normal: Received vehicle; Group 2: CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one; Group 3: NJ treatment: Received NJ (360 mg/b.w. p.o.) once daily for 14 days. Group 4: DNG treatment: DNG (360 mg/b.w. p.o.) once daily for 14 days, Group 5: NJ + CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one and after half an hour of received NJ (360 mg/b.w. p.o.) once daily for 14 days. Group 6: DNG + CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one and after half an hour received DNG (360 mg/b.w. p.o.) once daily for 14 days. Mice were subjected to the Morris water maze (MWM) challenge for two weeks as part of a behavioral study. Short-term memory impairment was observed in the behavioral activity of CYL-treated mice in the MWM test in the 1st week trial, and this effect was reversed in the 2nd week trial in the combination treatment group. The behavioral analysis proved that noni supplementation reduced the risk of memory impairment caused by CYL. Biochemical analysis revealed that CYL markedly increased the levels of AChE and MDA in brain tissue. Similarly, decreases in the levels of antioxidants, i.e., GSH, CAT, SOD and GST, were detected in the brain tissue of the mice exposed to CYL. Qualitative and quantitative examinations of histopathological examination of the mouse hippocampus supported the above findings. The results demonstrated that noni supplement therapy reversed the changes in the MDA, AChE, and antioxidant enzyme levels while improving the behavioral and histological alterations caused by CYL. Long-term hippocampal growth and memory are unaffected, suggesting that CYL is less harmful. According to our research, supplementing with noni in conjunction with CYL may be a helpful treatment strategy for treating memory impairment caused by CYL.

Prevalence of perturbed gut microbiota in pathophysiology of arsenic-induced anxiety- and depression-like behaviour in mice

Severe toxic effects of arsenic on human physiology have been of immense concern worldwide. Arsenic causes irrevocable structural and functional disruption of tissues, leading to major diseases in chronically exposed individuals. However, it is yet to be resolved whether the effects result from direct deposition and persistence of arsenic in tissues, or via activation of indirect signaling components. Emerging evidences suggest that gut inhabitants play an active role in orchestrating various aspects of brain physiology, as the gut-brain axis maintains cognitive health, emotions, learning and memory skills. Arsenic-induced dysbiosis may consequentially evoke neurotoxicity, eventually leading to anxiety and depression. To delineate the mechanism of action, mice were exposed to different concentrations of arsenic. Enrichment of Gram-negative bacteria and compromised barrier integrity of the gut enhanced lipopolysaccharide (LPS) level in the bloodstream, which in turn elicited systemic inflammation. Subsequent alterations in neurotransmitter levels, microglial activation and histoarchitectural disruption in brain triggered onset of anxiety- and depression-like behaviour in a dose-dependent manner. Finally, to confirm whether the neurotoxic effects are specifically a consequence of modulation of gut microbiota (GM) by arsenic and not arsenic accumulation in the brain, fecal microbiota transplantations (FMT) were performed from arsenic-exposed mice to healthy recipients. 16S rRNA gene sequencing indicated major alterations in GM population in FMT mice, leading to severe structural, functional and behavioural alterations. Moreover, suppression of Toll-like receptor 4 (TLR4) using vivo-morpholino oligomers (VMO) indicated restoration of the altered parameters towards normalcy in FMT mice, confirming direct involvement of the GM in inducing neurotoxicity through the arsenic-gut-brain axis. This study accentuates the potential role of the gut microbiota in promoting neurotoxicity in arsenic-exposed mice, and has immense relevance in predicting neurotoxicity under altered conditions of the gut for designing therapeutic interventions that will target gut dysbiosis to attenuate arsenic-mediated neurotoxicity.

Analytical Methodologies to Detect N-Nitrosamine Impurities in Active Pharmaceutical Ingredients, Drug Products and Other Matrices.

Since 2018, N-nitrosamine impurities have become a widespread concern in the global regulatory landscape of pharmaceutical products. This concern arises due to their potential for contamination, toxicity, carcinogenicity, and mutagenicity and their presence in many active pharmaceutical ingredients, drug products, and other matrices. N-Nitrosamine impurities in humans can lead to severe chemical toxicity effects. These include carcinogenic effects, metabolic disruptions, reproductive harm, liver diseases, obesity, DNA damage, cell death, chromosomal alterations, birth defects, and pregnancy loss. They are particularly known to cause cancer (tumors) in various organs and tissues such as the liver, lungs, nasal cavity, esophagus, pancreas, stomach, urinary bladder, colon, kidneys, and central nervous system. Additionally, N-nitrosamine impurities may contribute to the development of Alzheimer's and Parkinson's diseases and type-2 diabetes. Therefore, it is very important to control or avoid them by enhancing effective analytical methodologies using cutting-edge analytical techniques such as LC-MS, GC-MS, CE-MS, SFC, etc. Moreover, these analytical methods need to be sensitive and selective with suitable precision and accuracy, so that the actual amounts of N-nitrosamine impurities can be detected and quantified appropriately in drugs. Regulatory agencies such as the US FDA, EMA, ICH, WHO, etc. need to focus more on the hazards of N-nitrosamine impurities by providing guidance and regular updates to drug manufacturers and applicants. Similarly, drug manufacturers should be more vigilant to avoid nitrosating agents and secondary amines during the manufacturing processes. Numerous review articles have been published recently by various researchers, focusing on N-nitrosamine impurities found in previously notified products, including sartans, metformin, and ranitidine. These impurities have also been detected in a wide range of other products. Consequently, this review aims to concentrate on products recently reported to contain N-nitrosamine impurities. These products include rifampicin, champix, famotidine, nizatidine, atorvastatin, bumetanide, itraconazole, diovan, enalapril, propranolol, lisinopril, duloxetine, rivaroxaban, pioglitazones, glifizones, cilostazol, and sunitinib.

Biogenic zinc oxide nanoregulator determines the quantitative analysis of morpho-anatomical and antioxidant capacity in Lactuca sativa L.

Zinc oxide nanoparticles (ZnO NPs) can possibly serve as a pervasive source of essential nutrient zinc in agricultural crops in the future. The major environmental concerns with ZnO NPs might be their toxicity and incorrect dosage, which might lead to crop damage and environmental pollution. Interplay between ZnO NPs and Lactuca sativa (L. sativa) will be of interest, yet little is known about apropos interaction of these two, which will assist in optimizing the dose of ZnO NPs for their commercial use in agriculture. The current study aimed to investigate the growth, anatomical, and antioxidative responses of L. sativa against ZnO NPs and zinc acetate. ZnO NPs were foliar sprayed with concentrations of 0, 25, 50, and 100 ppm. ZnO NPs remarkably promoted L. sativa growth, leaf water content, and biomass accumulation; however, they declined root growth. The foliar spray of ZnO NPs improved the thickness of the stem hypodermis, cortex, pericycle, and phloem, while decreasing the stem diameter, thickness of the epidermis, and number of vascular bundles. ZnO NPs rigorously declined the cell area of xylem but slightly improved it in phloem. Unlike stem cells' anatomical responses to ZnO NPs, the root cells behaved otherwise. Overall, the antioxidative activity of L. sativa considerably improved at 25 ppm concentration and decreased at 100 ppm. Generally, low and medium concentrations of ZnO NPs promoted plant morphological, anatomical, and antioxidant traits, while higher doses inhibited the same traits. Contrary to this, Zn acetate displayed severe toxic effects on almost all studied anatomical traits.

The Bioremoval of Toxic Dyes Using Chlorella Algae in Airlift Bioreactor

<p style="text-align:justify; margin-bottom:11px"><span style="font-size:11pt"><span style="line-height:107%"><span style="font-family:Calibri,sans-serif"><span style="font-size:14.0pt"><span style="line-height:107%"><span style="font-family:"Times New Roman",serif">Malachite green (MG) and Crystal Violet (CV) are used mainly as dyestuff and antimicrobials in aquaculture. They have a severe toxic effect on the environment. Several techniques were used to remove impurities from an aqueous solution: chemical, physical, and electrical. Among all these techniques, using dry algae is a more economical and helpful process. This study aims to investigate using an airlift reactor in the removal of MG and CV by chlorella algae as a biosorbent under different variables. The experiments were carried out in an airlift bioreactor. The experiments were carried out under the effect different operating conditions of initial dye concentration (5-40 ppm), alga dosage (0.3-1.8 gm/l), pH (3–10), air flow rate (0-40 ml/min), temperature (298-318 K) and contact time (5-60 min).  The results show that the introduce of air bubbles significantly enhances the removal efficiency of the dye. The best removal effectiveness was 95.2% for MG dye and 96.1% for CV dye.  The thermodynamics results reveal that the processes are exothermic for both dyes. Kinetic and adsorption isotherms results show the best fit is pseudo-second order and Langmuir model. The mass model result shows that the liquid film diffusion model was the best-fitted for both dyes.</span></span></span></span></span></span></p>

In-Situ Grown Nanocrystal TiO2 on 2D Ti3C2 Nanosheets with Anti-Tumor Activity from Photo-Sonodynamic Treatment and Immunology.

Traditional cancer treatment strategies often have severe toxic side effects and poor therapeutic efficacy. To address the long-standing problems related to overcoming the complexity of tumors, we develop a novel nanozyme based on the in situ oxidation of 2D Ti3C2 structure to perform simultaneous phototherapy and sonodynamic therapy on tumors. Ti3C2 nanozymes exhibit multi-enzyme activity, including intrinsic peroxidase (POD) activities, which can react with H2O2 in the tumor microenvironment. This new material can construct Ti3C2/TiO2 heterostructures in vivo. Photothermal (PTT), sonodynamic (SDT) effects, and photoacoustic (PA) image-guided synergy therapy can be achieved. Finally, anticancer immune responses occur with this nanozyme. In vivo experiments revealed that the Ti3C2/TiO2 heterostructure inhibited tumor growth. Complementarily, our results showed that the Ti3C2/TiO2 heterostructure enhanced the immunogenic activity of tumors by recruiting cytotoxic T cells, thereby enhancing the tumor ablation effect. Mechanistic studies consistently indicated that Reactive Oxygen Species (ROS) regulates apoptosis of HCC cells by modulating NRF2/OSGIN1 signaling both in vitro and in vivo. As a result, Ti3C2 nanozyme effectively inhibited tumor through its synergistic ability to modulate ROS and enhance immune infiltration of cytotoxic T cells in the tumor microenvironment. These findings open up new avenues for enhancing 2D Ti3C2 nanosheets and suggest a new way to develop more effective sonosensitizers for the treatment of cancer.

Core-crosslinked polyprodrug nanoparticles via facile crosslinking-induced self-assembly for tumor intracellular acid-triggered doxorubicin delivery

Premature drug leakage from the drug delivery systems (DDSs) causes severe toxic side effects on the normal cells, restricting their practical application in tumor chemotherapy. Here, core-crosslinked polyprodrug nanoparticles were designed by facile crosslinking-induced self-assembly of polyethylene glycol-b-poly(p-formylphenyl methacrylate) (PEG-PFPMA) di-block copolymer via acid-labile Schiff base bonds, with a pH-responsive doxorubicin-doxorubicin dimer (Di-DOX-ADH) as crosslinker. Owing to the unique structure, the chemotherapeutic drug, doxorubicin (DOX), could be released only when the Schiff base bond and hydrazone bond on both sides of the DOX unit were cleaved. Thus, a leakage-free tumor intracellular acid-triggered on-demand drug release was achieved with cumulative DOX release of 80 % in the simulated tumor intracellular microenvironment in 80 h. The proposed core-crosslinked polyprodrug nanoparticles could be internalized by the HepG2 cells and released DOX therein, exhibiting an enhanced tumor growth inhibition than free DOX.

Targeted pH-responsive biomimetic nanoparticle-mediated starvation-enhanced chemodynamic therapy combined with chemotherapy for ovarian cancer treatment

In recent years, the use of arsenic trioxide (ATO) in the context of ovarian cancer chemotherapy has attracted significant attention. However, ATO’s limited biocompatibility and the occurrence of severe toxic side effects hinder its clinical application. A nanoparticle (NP) drug delivery system using ATO as a therapeutic agent is reported in this study. Achieving a synergistic effect by combining starvation therapy, chemodynamic therapy, and chemotherapy for the treatment of ovarian cancer was the ultimate goal of this system. This nanotechnology-based drug delivery system (NDDS) introduced arsenic-manganese complexes into cancer cells, leading to the subsequent release of lethal arsenic ions (As3+) and manganese ions (Mn2+). The acidic microenvironment of the tumor facilitated this process, and MR imaging offered real-time monitoring of the ATO dose distribution. Simultaneously, to produce reactive oxygen species that induced cell death through a Fenton-like reaction, Mn2+ exploited the surplus of hydrogen peroxide (H2O2) within tumor cells. Glucose oxidase-based starvation therapy further supported this mechanism, which restored H2O2 and lowered the cellular acidity. Consequently, this approach achieved self-enhanced chemodynamic therapy. Homologous targeting of the NPs was facilitated through the use of SKOV3 cell membranes that encapsulated the NPs. Hence, the use of a multimodal NDDS that integrated ATO delivery, therapy, and monitoring exhibited superior efficacy and biocompatibility compared with the nonspecific administration of ATO. This approach presents a novel concept for the diagnosis and treatment of ovarian cancer.

Coaxial nanofibrous aerogel featuring porous network-structured channels for ovarian cancer treatment by sustained release of chitosan oligosaccharide

Ovarian cancer, the deadliest gynecological malignancy, primarily treated with chemotherapy. However, systemic chemotherapy often leads to severe toxic side effects and chemoresistance. Drug-loaded aerogels have emerged as a promising method for drug delivery, as they can improve drug solubility and bioavailability, control drug release, and reduce drug distribution in non-targeted tissues, thereby minimizing side effects. In this research, chitosan oligosaccharide (COS)-loaded nanofibers composite chitosan (CS) aerogels (COS-NFs/CS) with a porous network structure were created using nanofiber recombination and freeze-drying techniques. The core layer of the aerogel has a COS loading rate of 60 %, enabling the COS-NFs/CS aerogel to significantly inhibit the migration and proliferation of ovarian cancer cells (resulting in a decrease in the survival rate of ovarian cancer cells to 33.70 % after 48 h). The coaxial fiber's unique shell-core structure and the aerogel's porous network structure enable the COS-NFs/CS aerogels to release COS steadily and slowly over 30 days, effectively reducing the initial burst release of COS. Additionally, the COS-NFs/CS aerogels exhibit good biocompatibility, degradability (only retaining 18.52 % of their weight after 6 weeks of implantation), and promote angiogenesis, thus promoting wound healing post-oophorectomy. In conclusion, COS-NFs/CS aerogels show great potential for application in the treatment of ovarian cancer.

The fabrication of a hybrid fluorescent nanosensing system and its practical applications via film kits for the selective determination of mercury ions

Heavy metal ions especially mercury exposure have severe toxic effects on living organisms and human health. Therefore, easy, accessible, and accurate determination strategies for the selective specification of mercury ions are essential for numerous disciplines. In the presented paper, new hybrid fluorescent iron oxide nanoparticles labeled with carbazole and triazole units (CT-IONP) were prepared via surface modification for the spectrofluorimetric determination of Hg2+ in environmental samples. The structure of the new sensing system is characterized via various spectroscopic, thermal, and microscopic techniques. Under optimized conditions, the hybrid system is not only used in fully water media but also highly fluorescent which led to the “turn-off” response towards Hg2+ ion in the presence of various competitive species. The presented sensing system was successfully used for the determination of Hg2+ ions in the wide linear working range (0.02–10.00 µmol.L−1) at nanomolar levels, where the limit of detection and quantification were calculated as 7.38 and 22.14 nmol.L−1. Importantly, the practical application of hybrid material was applied by CT-IONP embedded polycaprolactone (PCL) polymer film kits. The bluish color of fabricated film kits was instantly and dramatically turned colorless-dark patterns after the addition of Hg2+ ions, which resulted in convenient and rapid film test kits for selective detection.

Cinnamon nanoemulsion mitigates acetamiprid-induced hepatic and renal toxicity in rats: biochemical, histopathological, immunohistochemical, and molecular docking analysis

Acetamiprid (ACDP) is a widely used neonicotinoid insecticide that is popular for its efficacy in controlling fleas in domestic settings and for pets. Our study aims to offer a comprehensive examination of the toxicological impacts of ACDP and the prophylactic effects of cinnamon nanoemulsions (CMNEs) on the pathological, immunohistochemical, and hematological analyses induced by taking ACDP twice a ‎week for 28 days. Forty healthy rats were divided into four groups (n = 10) at random; the first group served as control rats; the second received CMNEs (2 mg/Kg body weight); the third group received acetamiprid (ACDP group; 21.7 mg/Kg body weight), and the fourth group was given both ACDP and CMNEs by oral gavage. Following the study period, tissue and blood samples were extracted and prepared for analysis. According to a GC-MS analysis, CMNEs had several bioactive ingredients that protected the liver from oxidative stress by upregulating antioxidant and anti-inflammatory agents. Our findings demonstrated that whereas ACDP treatment considerably boosted white blood cells (WBCs) and lymphocytes, it significantly lowered body weight gain (BWG), red blood cells (RBCs), hemoglobin (Hb), hematocrit (HCT), and platelets (PLT). ACDP notably reduced antioxidant enzyme activities: superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) and elevated hydrogen peroxide and malondialdehyde levels compared with other groups. ACDP remarkably raised alanine aminotransferase (ALT), aspartate amino transaminase (AST), and alkaline phosphatase (ALP) levels.Moreover, the histopathological and immunohistochemistry assays discovered a severe toxic effect on the liver and kidney following ACDP delivery. Furthermore, cyclooxygenase 2 (COX-2) + immunoexpression was enhanced after treatment with CMNEs. All of the parameters above were returned to nearly normal levels by the coadministration of CMNEs. The molecular docking of cinnamaldehyde with COX-2 also confirmed the protective potential of CMNEs against ACDP toxicity. Our findings highlighted that the coadministration of CMNEs along with ACDP diminished its toxicity by cutting down oxidative stress and enhancing antioxidant capacity, demonstrating the effectiveness of CMNEs in lessening ACDP toxicity.

T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation

P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer. This study established drug-resistant cell models and animal models. Subsequently, comprehensive evaluations involving cell uptake, cell apoptosis, cellular toxicity assays, in vivo tumor-targeting capability, and anti-tumor activity assays were conducted to assess the drug resistance reversal effects of T7-MLP@DTX/SchB. Additionally, a systematic assessment of the biosafety profile of T7-MLP@DTX/SchB was executed, including blood profiles, biochemical markers, and histopathological examination. It was found that this co-delivery strategy successfully exerted the synergistic effects, since there was a significant tumor growth inhibitory effect on multidrug-resistant breast cancer. Targeted modification with T7 peptide enhanced the therapeutic efficacy remarkably, while vastly ameliorating the biocompatibility compared to free drugs. The intriguing results supported the promising potential use of T7-MLP@DTX/SchB in overcoming MDR breast cancer treatment.

Ethanol extract of Ziziphus nummularia ameliorates formaldehyde-induced arthritis in rats by regulating oxidative stress biomarkers and haematological profile.

Rheumatoid arthritis is an autoimmune inflammatory disorder that mainly affects bone and cartilage architecture. The continuous use of NSAIDs and DMARDs is associated with severe toxic effects. Therefore, the current study was designed to scrutinize herb-based therapy for the treatment of RA. To evaluate the anti-arthritic activity of ethanol extract of Ziziphus nummularia using formaldehyde-induced arthritic model in rats and elucidate the possible mechanism for anti-arthritic activity. Anti-arthritic activity of ETZN was studied at three oral doses, i.e., 200, 400, and 600mg/kg. Selected doses were studied using various clinical parameters viz. paw volume, inflammatory index, motility test, stair test, anti-nociceptive efficacy, walking track analysis, and motor activity) from day 1 to day 10. On the last day, the animals were killed for the evaluation of hematological parameters, oxidative stress biomarkers, and histological and radiographic studies of the hind paw. Treatment with ETZN 400mg/kg and 600mg/kg markedly elicited a significant reduction in paw volume, inflammatory index, and nociceptive action compared to diseased animals. Furthermore, the anti-inflammatory activity was confirmed by increased latency of pain threshold in thermal and mechanical algesia models. The anti-arthritic activity is mainly attributed to a reduction in oxidative stress biomarkers as well as restoration of haematological profile in treated animals when compared to diseased animals. Lastly, the anti-arthritic potential was confirmed by histological and radiological analysis which revealed a marked reduction in inflammatory cells and bone destruction as compared to diseased animals. The study revealed that ETZN exhibits significant anti-arthritic activity via modulation of oxidative stress biomarkers, restoration of hematological profile, and reduction in bone erosion.

Removal of cadmium through biomineralization using halophilic and ureolytic bacteria under saline conditions

Heavy metal pollution poses an immense challenge to humanity owing to its severe toxic effects on living beings. This study investigates the bioremediation potential of the urease-hydrolyzing and halophilic bacterium Bacillus paramycoides- MSR1 to reduce the toxicity of cadmium (Cd) in the environment under salt stress through microbially induced calcium carbonate precipitation (MICCP). The enzymatic activity of urease and calcium carbonate (CaCO3) precipitation was studied under different concentrations of salt stress (0%, 3.5%, 5%, 7.5%, 10%, 15%) and maximum urease activity of 735.7 U/ml was recorded at 5% salt stress. The urease activity and CaCO3 precipitation decreased with increasing Cd toxicity (0, 10, 20, 30, 40, 50, and 60 μM). The maximum concentration of Cd endured by bacteria was determined by IC50 value and the minimum inhibitory concentration of Cd was recorded as 9.86 μM under 5% stress. Atomic absorption spectroscopy results revealed that Cd removal was as high as 90.3% under 5% salt stress. Microstructural analysis through FE-SEM revealed the surface topography of carbonate crystals as rhombohedral, whereas EDS confirmed the presence of CaCO3 and Cd in the bio-precipitates. These results suggest that MICCP is a potential, environmentally safe, low-cost technique and an excellent alternative to conventional heavy metal removal strategies from the environment.

Cinnamaldehyde /naringin co-loaded into lactoferrin/ casienate-coated zein nanoparticles as a gastric resistance oral carrier for mitigating doxorubicin-induced hepatotoxicity

Doxorubicin (DOX) is a potent anticancer drug with severe toxic side effects on vital organs. The main mechanism of DOX's toxicity includes overproduction of reactive oxygen species (ROS) causing extensive oxidative stress. In order to minimize DOX-induced hepatotoxicity, cinnamaldehyde (CNM) and naringin (NAR) were co-encapsulated into zein nanoparticles (NPs). Afterwards, the dual-loaded NPs were dual-coated with lactoferrin (LF) and sodium casieate (NaCAS) in order to resist the gastric acidity upon oral administration. CNM/NAR-loaded LF/NaCAS-coated zein NPs exhibited a double coated spherical shape with particle size of 268.5 ± 6.4 nm, zeta potential of −12 ± 1.1 mV, and EE% of 79.54 ± 4.3 for CNM and 73.61 ± 2.9 % for NAR. Moreover, dual drug-loaded LF/NaCAS-coated zein NPs demonstrated slow release of CNM and NAR in simulated gastric fluid (SGF) compared to NaCAS-coated NPs, free CNM and free NAR, resulting in enhanced bioavailability. In addition, the prepared formulation showed good physical stability and hemocompatibility. More importantly, when this formulation was orally administrated to DOX oxidative stress-induced mice, they showed improved liver architecture with reduced inflammation and better antioxidant potential with no signs of toxicity, suggesting a reduction in ROS-mediated damage. In conclusion, CNM/NAR-loaded LF/NaCAS-coated zein NPs might be administrated orally in patients receiving DOX as a natural supplement to reduce the detrimental effects of this potent cytotoxic drug.