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Abstract Collisions of the transcription and replication machineries on the same DNA strand can pose a significant threat to genomic stability. These collisions occur in part due to the formation of RNA-DNA hybrids termed R-loops, in which a newly transcribed RNA molecule hybridizes with the DNA template strand. This study investigated the role of RAD52, a known DNA repair factor, in preventing collisions by directing R-loop formation and resolution. We show that RAD52 deficiency increases R-loop accumulation, exacerbating collisions and resulting in elevated DNA damage. Furthermore, RAD52’s ability to interact with the transcription machinery, coupled with its capacity to facilitate R-loop dissolution, highlights its role in preventing collisions. Lastly, we provide evidence of an increased mutational burden from double-strand breaks at conserved R-loop sites in human tumor samples, which is increased in tumors with low RAD52 expression. In summary, this study underscores the importance of RAD52 in orchestrating the balance between replication and transcription processes to prevent collisions and maintain genome stability.

Abstract Background Pathogenic BRCA1 or BRCA2 germline mutations contribute to hereditary breast, ovarian, prostate, and pancreatic cancer. Paradoxically, bi-allelic inactivation of BRCA1 or BRCA2 (bBRCA1/2) is embryonically lethal and decreases cellular proliferation. The compensatory mechanisms that facilitate oncogenesis in bBRCA1/2 tumors remain unclear. Methods We identified recurrent genetic alterations enriched in human bBRCA1/2 tumors and experimentally validated if these improved proliferation in cellular models. We analyzed mutations and copy number alterations (CNAs) in bBRCA1/2 breast and ovarian cancer from the TCGA and ICGC. We used Fisher’s exact test to identify CNAs enriched in bBRCA1/2 tumors compared to control tumors that lacked evidence of homologous recombination deficiency. Genes located in CNA regions enriched in bBRCA1/2 tumors were further screened by gene expression and their effects on proliferation in genome-wide CRISPR/Cas9 screens. A set of candidate genes was functionally validated with in vitro clonogenic survival and functional assays to validate their influence on proliferation in the setting of bBRCA1/2 mutations. Results We found that bBRCA1/2 tumors harbor recurrent large-scale genomic deletions significantly more frequently than histologically matched controls (n = 238 cytobands in breast and ovarian cancers). Within the deleted regions, we identified 277 BRCA1-related genes and 218 BRCA2-related genes that had reduced expression and increased proliferation in bBRCA1/2 but not in wild-type cells in genome-wide CRISPR screens. In vitro validation of 20 candidate genes with clonogenic proliferation assays validated 9 genes, including RIC8A and ATMIN (ATM-Interacting protein). We identified loss of RIC8A, which occurs frequently in both bBRCA1/2 tumors and is synthetically viable with loss of both BRCA1 and BRCA2. Furthermore, we found that metastatic homologous recombination deficient cancers acquire loss-of-function mutations in RIC8A. Lastly, we identified that RIC8A does not rescue homologous recombination deficiency but may influence mitosis in bBRCA1/2 tumors, potentially leading to increased micronuclei formation. Conclusions This study provides a means to solve the tumor suppressor paradox by identifying synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers.

Polyethylene microplastics (PEMPs) are toxic environmental contaminants which can impair multiple organs including heart. Sakuranetin (SKN) is a potential flavonoid with diverse pharmacological benefits. This research was undertaken to analyze the defensive impact of SKN to avert PEMPs-induced cardiotoxicity. 24 male albino rats were randomly allocated into 4 separate groups: control, PEMPs (1.5 mg kg−1), PEMPs + SKN (1.5 mg kg−1 + 10 mg kg−1) and only SKN (10 mg kg−1) treated group. After 30 days of treatment, our results revealed that PEMPs exposure reduced the expressions of Nrf2 and antioxidant genes while increasing Keap1 expression. Besides, PEMPs intoxication escalated the levels of cardiac markers (CPK, LDH, Troponin I & CK-MB). Additionally, it lessened the activities of GSH, GST, SOD, HO-1, CAT, GSR, GPx whereas the levels of MDA and ROS were increased. Conversely, the levels of inflammatory markers i.e., COX-2 activity IL-1β, TNF-α, NF-kB & IL-6 were augmented. Moreover, the expressions of apoptotic markers i.e., Bax and caspase-3 were elevated while the Bcl-2 expression was decreased. However, SKN treatment significantly restored the PEMPs-induced biochemical dysregulations. Therefore, SKN could be used as a therapeutic compound to ameliorate PEMPs-induced cardiac impairments in rats, possibly due to its tremendous pharmacotherapeutic potential.

Malathion (MLT) is an organophosphate pesticide that instigates severe injuries in the testicular tissues. Tangeretin (TGN) is an important naturally present flavone that shows potential antioxidant and anti-apoptotic activities. This research was planned to ascertain the palliative role of TGN against MLT-instigated testicular toxicity in male Sprague-Dawley (SD) rats. 48 rats were distributed into 4 groups: control, MLT (100 mgkg−1), MLT+TGN (100 + 50 mgkg−1 respectively), and TGN (50 mgkg−1). The results showed that MLT exposure reduced the activities of catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH), whereas escalated the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Moreover, it decreased the levels of luteinizing hormone (LH), plasma testosterone, and follicle-stimulating hormone (FSH). MLT also reduced the expressions of steroidogenic enzymes, including StAR, 3β-HSD, and 17β-HSD. Additionally, MLT exposure increased the expressions of Bax and Caspase-3, while reducing the Bcl-2 expressions. MLT administration also increased the levels of inflammatory markers such as nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (1L-1β) as well as cyclooxygenase-2 (COX-2) activity in testes. Nonetheless, TGN recovered all the MLT induced damages in testes. In conclusion, TGN could ameliorate MLT instigated testicular impairment because of its anti-apoptotic, androgenic and anti-oxidant properties.

Polystyrene microplastics (PS-MPs) are raising global concerns as they have tendency to induce adverse effects on organisms. Herbacetin (HBN) is a natural flavone that shows diverse biological activities. Therefore, the current study was designed to evaluate the curative role of HBN against PS-MPs provoked hepatic damage. Forty-eight rats were divided into 4 groups, control, PS-MPs-intoxicated (0.01 mg/kg), PS-MPs + HBN co-treated (0.01 mg/kg + 40 mg/kg) and HBN only treated (40 mg/kg) group. The experiment was conducted for 30 days. PS-MPs administration reduced the expressions of Nrf-2 as well as anti-oxidants genes and increased Keap-1 expression. It also lessened the activities of superoxide dismutase (SOD), glutathione reductase (GSR), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and heme oxygenase-1 (HO-1) and glutathione (GSH) level, while elevating the levels of MDA and ROS. Additionally, PS-MPs exposure augmented the levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine transaminase (ALT). Furthermore, there was an upsurge in the levels of inflammatory indices in PS-MPs treated group. PS-MPs also upregulated Caspase-3 and Bax expression whereas, decreased Bcl-2 expression. Nevertheless, HBN treatment recovered all the impairments due to its anti-apoptotic, anti-oxidant and anti-inflammatory and hepatoprotective nature. Therefore, it is deduced that HBN could be used as a potential therapeutic agent to counter PS-MPs induced hepatic toxicity.

Polystyrene microplastics (PS-MPs) are environmental toxicants that exert adverse effects on organisms. Rhamnetin (RHM) is a natural flavone that shows multiple therapeutic potentials. Therefore, the present study was planned to determine the mitigative effect of RHM against PS-MPs induced liver damage. 48 rats were divided into 4 groups. Control group, PS-MPs (0.01 mg/kg) administered group, PS-MPs (0.01 mg/kg)+ RHM (50 mg/kg) co-administered group and RHM alone (50 mg/kg) administered group. PS-MPs reduced the expressions of Nrf-2 and anti-oxidant gene expressions, while increasing Keap-1 expression. PS-MPs also decreased the activities of catalase (CAT), glutathione reductase (GSR), heme oxygenase-1 (HO-1), glutathione-S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH), besides elevating the levels of MDA and ROS. Additionally, PS-MPs augmented the levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and aspartate aminotransferase (AST). Furthermore, there was an upsurge in the levels of inflammatory indices in PS-MPs treated group. PS-MPs intoxication also increased Bax and Caspase-3 expressions, while lowering the Bcl-2 expression. Nevertheless, RHM mitigated all the damages due to its hepatoprotective, anti-inflammatory, anti-oxidant and anti-apoptotic potentials.

Polystyrene microplastics (PSMPs) have emerged as potentially hazardous materials, which significantly affect various body organs including kidneys. Narirutin (NRT) is a flavanone that exhibits a wide range of pharmacological properties. Therefore, this study was planned to appraise the nephro-protective effects of NRT on PSMPs-instigated kidney damages in male albino rats. In this study, 24 male albino rats were randomly distributed in 4 groups (n = 6/group); control group, PSMPs (0.01 mgkg−1) treated group, PSMPs + NRT (0.01 mgkg−1 + 50 mgkg−1) co-treated group, and NRT (50 mgkg−1) only treated group. PSMPs exposure reduced the expressions of Nrf-2 and anti-oxidant enzymes coupled with increased expressions of Keap-1. PSMPs treatment reduced the activities of heme oxygenase-1 (HO-1), catalase (CAT), glutathione reductase (GSR), glutathione peroxidase (GPx), glutathione (GSH), glutathione S-transferase (GST), and superoxide dismutase (SOD), whereas escalated the levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Moreover, PSMPs administration substantially elevated the levels of kidney function markers such as creatinine, urea, kidney injury molecules-1 (KIM-1) and neutrophil gelatinase associated lipocalin (NGAL). Conversely, it reduced the level of creatinine clearance. Besides, PSMPs significantly escalated the levels of inflammatory markers such as nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and cyclooxygenase-2 (COX-2) activity. In contrast, NRT restored all these damages and abnormalities to their normal level. According to these findings, NRT may act as a potential flavanone with the ability to mitigate the kidney toxicity induced by PSMPs in male albino rats.

Doxorubicin (DOX) is a potent chemotherapeutic agent that is used in various sorts of malignancies. However, its uses are restricted owing to its deleterious effects on different organs including the liver. Cupressuflavone (CUP) is a plant-based flavonoid which is well known for its biological as well pharmacological potential. Our investigation aimed to evaluate the ameliorative potential of CUP against DOX provoked liver toxicity in rats. Twenty-four albino rats (Rattus norvegicus) were distributed into four distinct groups such as control, DOX (3 mg/kg), co- administrated DOX (3 mg/kg) + CUP (40 mg/kg) and CUP (40 mg/kg) only. DOX exposure reduced catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), Glutathione reductase (GSR), glutathione-S-transferase (GST) activities and glutathione (GSH) content while escalating the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Besides, the levels of ALT, AST and ALP were increased in response to DOX exposure. Furthermore, administration of DOX upregulated the levels of Interleukin-6 (IL-6), Nuclear factor kappa-B (NF-κB), Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and the activity of cyclooxygenase-2 (COX-2). The treatment of DOX reduced the levels of Bcl-2 while escalating the levels of Caspase-3, Caspase-9 and Bax. Similarly, DOX intoxication instigated various histopathological disruptions in hepatic tissues of rats. However, supplementation of CUP notably (p

Arsenic is a lethal toxicant found ubiquitously in the ecosystem which adversely affects the body organs including the heart. Pachypodol (PCHP) is a natural flavone which exhibits substantial pharmacotherapeutic potentials. The rats (n = 24) were distributed into 4 different groups i.e., control, arsenic-intoxicated group (50 mg/kg), arsenic + PCHP-supplemented group (50 mg/kg + 10 mg/kg) & PCHP-treated (10 mg/kg) group. It was assessed that arsenic administration subsided catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), glutathione peroxidase (GPx), & glutathione S-transferases (GST) activities while augmenting the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Furthermore, arsenic exposure increased the levels of cardiac injury markers such as creatine phosphokinase (CPK), creatine kinase-MB (CK-MB), troponin I & lactate dehydrogenase (LDH). Besides, the levels of inflammatory markers nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), Tumor necrosis factor α (TNF-α), Interleukin 6 (IL-6) levels and cyclooxygenase 2 (COX-2) activity were increased following the arsenic exposure. Similarly, Caspase-3, Bax and Caspase-9 levels were upsurged whereas Bcl-2 level was reduced after arsenic intoxication. In addition, the histopathological assessment revealed a substantial cardiac tissues impairment in the arsenic exposed group. Nonetheless, PCHP supplementation substantially (p

Abstract Melanoma response to immune-modulating therapy remains incompletely characterized at the molecular level. In this study, we assess melanoma immunotherapy response using a multi-scale network approach to identify gene modules with coordinated gene expression in response to treatment. Using gene expression data of melanoma before and after treatment with nivolumab, we modeled gene expression changes in a correlation network and measured a key network geometric property, dynamic Ollivier-Ricci curvature, to distinguish critical edges within the network and reveal multi-scale treatment-response gene communities. Analysis identified six distinct gene modules corresponding to sets of genes interacting in response to immunotherapy. One module alone, overlapping with the nuclear factor kappa-B pathway (NFkB), was associated with improved patient survival and a positive clinical response to immunotherapy. This analysis demonstrates the usefulness of dynamic Ollivier-Ricci curvature as a general method for identifying information-sharing gene modules in cancer.

Paraquat (PQ) an herbicide that is commonly used to remove undesirable grasses. However, PQ also causes cardiac damage through reactive oxygen species (ROS) production. Didymin (DYD) is a dietary flavone, present in citrus fruits and campanula. DYD displays multiple therapeutic activities i.e., anti-oxidant, hepatoprotective, neuroprotective and free radical salvaging. Therefore, the present study was planned to explore the ameliorative effect of DYD against PQ instigated cardiac damage. 24 rats were separated into 4 groups, control, PQ administered PQ + DYD co-administered orally and DYD only administered group. PQ intoxication significantly reduced anti-oxidants including (SOD, GST, GSH, CAT, GPx and GSR activities, while increasing malondialdehyde (MDA) and ROS levels. PQ intoxication escalated the level of cardiac injury marker i.e., creatine kinase myoglobin binding (CK-MB), troponin, creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH). PQ also augmented inflammatory markers i.e., (TNF-α, IL-1β, NF-κB, IL-6 levels and COX-2 activity). Moreover, PQ intoxication escalated the apoptotic proteins levels (Bax, Caspase-3 and Caspase-9), while decreasing Bcl-2 level. PQ intoxication also prompted histomorphological anomalies in the heart of rats. Conversely, DYD therapy restored all the anomalies and structural abnormalities owing to its cardioprotective potentials.

The optoelectronic devices play a crucial role in our daily lives by seamlessly integrating optics and electronics, enabling technologies like smartphones, solar cells, and optical communication. Solar cells have been very vital in terms of providing sustainable and clean energy. Conventional Perovskite-based solar cells possess limitations like stability and toxicity. Recently, ABO4-type materials have gained attention in optoelectronic devices due to their structural stability and suitable optoelectronic properties for solar cell applications. The structural, electronic, and optical properties of AgWO4 and PdWO4 have been explored using the first principal simulations in line with density functional theory (DFT) using WIEN2K simulation software. The Perdew-Burke-Ernzerhof Generalized-Gradient-Approximation (PBE-GGA) is acclimated to optimize the geometry of both materials under consideration. Trans-Balha modified Becke-Johnson approximation (TB-mBJ) approximation is implemented to study materials' optoelectronic properties. Structural analysis revealed the stable structure of AgWO4 and PdWO4 in the monoclinic phase with increasing lattice parameters and decreased unit cell volume upon replacement of Ag with Pd cation on the A site. Both materials ' negative values of ground state energies indicate the stability of both compounds. Upon analysis of the band structure of AgWO4 and PdWO4, it is found that both materials possess a band gap of 1.34eV and 0.73eV,respectively, signifying that both materials under consideration are semiconductors, with a potential for a controlled flow of electrical charges, coming up with promising various optoelectronic applications. Optical characteristics were explored and examined in depth in the framework of hypothetical dielectric constant. It has been discovered that the dielectric function has a broad span of energy integrity when it comes to its dielectric function. Materials with narrow bandgaps and excellent UV light absorption were found suitable for optoelectronic and solar cell applications.

Cisplatin (CP) is a ubiquitous antineoplastic medicine that has been recognized to have sever toxic effects on different organs including lungs. Rhoifolin (RHO) is a therapeutic compound with significant pharmacological activities. The present study was designed to evaluate the protective effect of RHO against CP induced pulmonary toxicity. Twenty-four rats were randomly divided into 4 groups: control group, CP treated group (20 mgkg−1), CP + RHO treated group (20 mgkg−1 + 10 mgkg−1) and RHO supplemented group (10 mgkg−1). Following 30 days of administration, our results showed that CP treatment decreased the activity of antioxidant enzymes such as glutathione (GSH), glutathione reductase (GSR), glutathione peroxidase (GPx), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) while elevated the level of malondialdehyde (MDA) along with reactive oxygen species (ROS). Furthermore, levels of inflammatory cytokines involving interleukin-6 (IL-6), nuclear factor-kappa B (NF-κB), interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α) and cyclo-oxygenase-2 (COX-2) activity were escalated. Besides, treatment with CP enhanced the activities of apoptotic proteins i.e., Bax, caspase-9 along with caspase-3 while reducing the activity of Bcl-2. Additionally, the histopathological examination revealed significant pulmonary tissue impairments in the CP exposed group. However, RHO treatment considerably (P

Cadmium (Cd) is a noxious and non-biodegradable heavy metal which instigates various organ toxicities such as cardiac injuries. Pinostrobin (PSB) is a potent dietary bioflavonoid, which shows various pharmacological potentials. The current research was designed to evaluate the ameliorative effects of PSB against Cd elicited cardiac dysfunction in rats. Twenty-four albino rats were apportioned into four equal groups viz. control, Cd (5 mg/kg), Cd (5 mg/kg) + PSB (40 mg/kg) and PSB (40 mg/kg) only treated group. It was observed that Cd intoxication reduced catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), glutathione peroxidase (GPx), activities and glutathione S-transferase (GST) contents while escalating the levels of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and malondialdehyde (MDA). Furthermore, Cd exposure escalated the levels of cardiac injury markers such as creatine phosphokinase (CPK), creatine kinase-myocardial band (CK-MB), troponin I and lactate dehydrogenase (LDH). Besides, the levels of inflammatory cytokines nuclear factor- κB (NF-κB), interleukin 1beta (IL-1ß), tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activity were upregulated in Cd intoxicated group. Similarly, Caspase-3, Bax and Caspase-9 levels were augmented, and Bcl-2 levels were reduced after Cd administration. In addition, the histopathological examination revealed a notable cardiac tissue impairment in the Cd exposed group. Nonetheless, PSB treatment significantly (p

Background: Paraquat (PQ) is a herbicide that is used globally in the agriculture sector to eradicate unwanted weeds, however it also induces significant damages in various organs of the body such as testes. Tectochrysin (TEC) is an important flavonoid that shows versatile therapeutic potentials. Currently, there is no established antidote to cure PQ-induced testicular toxicity. Objective: The present study was conducted to evaluate the ameliorative effects of TEC against PQ prompted testicular damage. Methods: Sprague-Dawley rats (n = 48) were used to conduct the trial. Rats were allocated in to 4 groups i.e., Control, PQ administrated group (5 mgkg−1), PQ + TEC co-administrated group (5 mgkg−1 + 2.5 mgkg−1) and TEC only administrated group (2.5 mgkg−1). The trial was conducted for 8 weeks. The activity of anti-oxidants and the levels of MDA and ROS were determined by spectrophotometric method. Steroidogenic enzymes as well as apoptotic markers expressions were evaluated by qRT-PCR. The level of hormones and inflammatory indices was quantified by enzyme-linked immunosorbent assay. Results: PQ exposure markedly (P

ABSTRACTHuman papilloma virus (HPV)-related oncogenesis in head and neck cancer establishes a local microenvironment rich with immune cells, however the composition of the microenvironment in recurrent disease following definitive treatment is poorly understood. Here, we investigate the composition and spatial relationships between tumor and immune cells in recurrent head and neck cancer following curative intent chemoradiotherapy. Multiplexed immunofluorescence with 12 unique markers, through two multiplex immunofluorescent panels, was performed to evaluate 27 tumor samples including 18 pre-treatment primary and 9 paired recurrent tumors. Tumor and immune cell populations were phenotyped and quantified using a previously validated semi-automated digital pathology platform for cell segmentation. Spatial analysis was conducted by evaluating immune cells within the tumor, peri-tumoral stroma, and distant stroma. Initial tumors in patients with subsequent recurrence were found to be enriched in tumor associated macrophages and displayed an immune excluded spatial distribution. Recurrent tumors after chemoradiation were hypo-inflamed, with a statistically significant reduction in the recently identified stem-like TCF1+ CD8 T-cells, which normally function to maintain HPV-specific immune responses in the setting of chronic antigen exposure. Our findings indicate that the tumor microenvironment of recurrent HPV-related head and neck cancers displays a reduction in stem-like T cells, consistent with an immune microenvironment with a reduced ability to mount T-cell-driven anti-tumor immune responses.

Cadmium (Cd) is an environmental and industrial toxicant that possess the ability to cause severe health issues to humans and animals. The flavonol, kaempferide (KF), exhibits multiple pharmacological potentials. Therefore, this investigation was designed to estimate the mitigative effect of KF against Cd instigated hepatic damage in rats. 24 albino rats (male) were kept in 4 different groups. The group-1 was designed as untreated/control group, group-2 was orally provided with Cd (5 mg/kg), group-3 was orally co-administrated with Cd (5 mg/kg) along with KF (20 mg/kg) and group-4 was supplemented with KF (20 mg/kg) during 30 days of trial. Cd administration significantly escalated ALT, ALP as well as AST levels. A substantial decline in SOD, GST, POD, CAT, GSR activities and GSH content was observed due to Cd exposure along with an elevation in TBARS and H2O2 levels. Moreover, Cd administration elevated NF-kB, IL-6, TNF-α as well as IL-1β levels in addition to the activity of COX-2. Furthermore, the levels of Bax, Caspase-9 as well as Caspase-3 were escalated, besides the level of Bcl-2 was decreased after Cd exposure. A significant increase in histopathological damages after Cd administration is a clear indication of liver damage. However, co-treatment of KF with Cd potential recovered all the damages and significantly reduced the biochemical and histological variations in rat liver. Overall results indicated that KF has efficient anti-oxidant properties, which mitigated Cd instigated hepatic damage in rats.

The present study focused on evaluating the influence of ultrasonic-assisted pasteurization (UAP) on the quality and shelf stability of jambul squash. Squash was analyzed for physicochemical characteristics during a storage period of 4 months. There was a significant effect (p

Gentamicin (GEN) is an extensively used aminoglycoside. Contrary to its antibacterial potential, it can induce oxidative stress in several organs, including kidney. Amentoflavone (AMN) is a biflavonoid with conspicuous pharmacological activities. The current study was held to estimate the curative efficacy of AMN to antagonize the nephrotoxic effects instigated by GEN. 48 albino rats were separated into four groups: control group, GEN administrated group (80 mgkg−1 intraperitoneally), GEN + AMN treated group (80 mgkg−1 + 40 mgkg−1) and only AMN administrated group (40 mgkg−1). Following 30 days of administration, results showed that GEN disturbed antioxidant enzymes i.e., glutathione (GSH), glutathione reductase (GSR), glutathione peroxidase (GPx), glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) activity, besides elevated malondialdehyde (MDA) along with reactive oxygen species (ROS) level. Besides this, level of inflammatory cytokines involving interleukin-6 (IL-6), nuclear factor-kappa B (NF-κB), interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α) & cyclo-oxygenase-2 (COX-2) were escalated. Furthermore, treatment with GEN enhanced the level of apoptotic proteins comprising of Bax, caspase-9 along with caspase-3 besides lessened the level of Bcl-2. In addition to this, GEN reduced the level of albumin, creatinine clearance & augmented the level of creatinine, urea, urobilinogen, urinary protein, kidney injury molecules-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) as well as instigated various histopathological damages. However, co-treated group (AMN + GEN) revoked abovementioned renal dysregulations instigated by GEN. Taken together, AMN could significantly counteract GEN-instigated nephrotoxic effects due to its antioxidant capabilities.

BACKGROUND Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is generally an incurable disease, with patients experiencing median survival of under 10 months and significant morbidity. While immune checkpoint blockade (ICB) drugs are effective in approximately 20% of patients, the remaining experience limited clinical benefit and are exposed to potential adverse effects and financial costs. Clinically approved biomarkers, such as tumor mutational burden (TMB), have a modest predictive value in HNSCC.METHODS We analyzed clinical and genomic features, generated using whole-exome sequencing, in 133 ICB-treated patients with R/M HNSCC, of whom 69 had virus-associated and 64 had non-virus-associated tumors.RESULTS Hierarchical clustering of genomic data revealed 6 molecular subtypes characterized by a wide range of objective response rates and survival after ICB therapy. The prognostic importance of these 6 subtypes was validated in an external cohort. A random forest-based predictive model, using several clinical and genomic features, predicted progression-free survival (PFS), overall survival (OS), and response with greater accuracy than did a model based on TMB alone. Recursive partitioning analysis identified 3 features (systemic inflammatory response index, TMB, and smoking signature) that classified patients into risk groups with accurate discrimination of PFS and OS.CONCLUSION These findings shed light on the immunogenomic characteristics of HNSCC tumors that drive differential responses to ICB and identify a clinical-genomic classifier that outperformed the current clinically approved biomarker of TMB. This validated predictive tool may help with clinical risk stratification in patients with R/M HNSCC for whom ICB is being considered.FUNDING Fundación Alfonso Martín Escudero, NIH R01 DE027738, US Department of Defense CA210784, The Geoffrey Beene Cancer Research Center, The MSKCC Population Science Research Program, the Jayme Flowers Fund, the Sebastian Nativo Fund, and the NIH/NCI Cancer Center Support Grant P30 CA008748.

Cisplatin (CP) is a top-notch anti-cancerous agent that is used during the treatments of various types of tumors. Tamarixetin (TM) is a naturally occurring polyphenolic compound with versatile therapeutic and pharmacological abilities. The current investigation was purposed to elucidate the antagonistic effects of TM against CP-prompted renal intoxication. Sprague Dawley rats (n = 48) were separated into 4 equal groups i.e., Group 1st was designated as control group while the 2nd group was treated with CP (10 mg/kg) only, group 3rd received CP (10 mg/kg) + TM (50 mg/kg) and designated as a co-treated group while group 4th was administered with TM (50 mg/kg) only. Our results revealed that treatment of CP reduced the activity of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione-disulfide reductase (GSR), glutathione S-transferase (GST) as well as glutathione (GSH) while elevate ROS and MDA levels. CP administration raised the level of urea, creatinine, KIM1 along with NGAL while significant reduction in creatinine clearance. Whereas, CP treatment substantially elevated the level of caspase-3, caspase- 9 and Bcl-2 associated X protein (Bax) while reducing the level of B cell lymphoma protein 2 (Bcl-2). CP administration significantly elevated the concentration of nuclear factor kappa-B (NF-kB), interleukin 6 (IL-6), interleukin 1 beta (IL-1β) as well as tumor necrosis factor α (TNF-α), and instigated histopathological damages in renal tissues. However, Co-treatment of CP + TM showed palliative effects against CP-induced impairments. The current study manifested that TM is a potential flavonoid that could be used as a therapeutic drug to ameliorate renal damages instigated by CP.

Myiasis is an ectoparasitic infestation caused by larvae of arthropods in the group Diptera. Cutaneous myiasis is the infection of skin and includes the following types: furuncular, migratory and wound myiasis. Out of all the organisms responsible for this disease, Wohlfahrtia vigil is the most common causative agent in Pakistan, usually seen from June to September with nearly all presentations occurring at a young age. In our case, a patient without a history of trauma, skin erosion or animal exposure has a unique presentation of cutaneous myiasis. Here, an effort was made to treat a 15-year-old otherwise healthy female with a multisegmented treatment modality. A follow up visit was conducted every three days for three months at the end of which a 60% decrease in the size of the open wound was observed. Keywords: Myiasis, ulcer, Pakistan.

Glabridin (GB) is a natural dietary flavonoid of plant origin with excellent antioxidant properties. Gentamicin (GM) is an aminoglycoside antibiotic that can potentially cause renal toxicity. This investigation was intended to elucidate the attenuative effects of GB against GM-instigated nephrotoxicity. The entire experiment was carried out for a week on adult male albino rats (n = 24), which were randomly separated into 4 comparable groups that included Group I (0.9% physiological saline), group II (80 mg/kg of GM i.p.), group III (80 mg/kg; 50 mg/kg of GM + GB respectively), and group IV (50 mg/kg of GB orally). Biochemical analysis of antioxidant enzymes i.e., superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione reductase (GSR), Glutathione-S-transferase (GST), glutathione (GSH), reactive oxygen species (ROS), hydrogen peroxide (H2O2), thiobarbituric acid reactive substance (TBARS) level, renal serum neutrophil gelatinase-associated lipocalin (NGAL) as well as kidney injury molecule-1 (KIM-1) along with urinary profile (Albumin, creatinine, urea, urinary protein, urobilinogen, and creatinine clearance), inflammatory markers (nuclear factor (NF)-κB, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interleukin (IL)-6 as well as cyclo-oxygenase (COX)-2), apoptotic markers (Bax, Caspase-3 as well as Caspase-9), anti-apoptotic markers (Bcl-2) as well as histopathology of renal tissues, were analyzed. GM significantly reduced antioxidant enzymes activity, on the other hand, GM treatment substantially elevated the concentration of ROS, H2O2, TBARS, as well as induced abnormality in renal serum markers and urine profile, inflammatory markers, pro-apoptotic markers whereas, declined the level of anti-apoptotic markers and induced substantial histopathological damages. However, GB treatment potentially alleviated damages caused by GM. Conclusively, the intriguing outcomes of the investigation propose that GB effectively protects against GM-prompted nephrotoxicity, which may indicate its anti-oxidant, anti-apoptotic as well as anti-inflammatory potential.

Bismuth Vanadate (BiVO4) has been synthesized using simple hydrothermal technique while varying the pH of concentrated H2SO4. With the increase of pH values (from 06 to 10), the morphology of the synthesized material tuned in the form of nano-spheres and cubes in the range from 50 to 60 nm. The lateral affect tuned the bandgap of BiVO4 from 2.47 eV to 2.50 eV which is significant in the context of present study. It is worth mentioning that desirous bandgap corresponds to the visible spectrum of the solar light being abundantly available and finds many applications in real life. The synthesized nanomaterial BiVO4 has been characterized through UV–Vis spectroscopy, X-ray diffraction, Scanning electron microscope and energy-dispersive X-ray (EDX) spectroscopy. The synthesized BiVO4 has been tested as photocatalyst for degradation of industrial pollutant from Leather Field Industry. Said catalyst (BiVO4) successfully degraded the industrial pollutant after 3 h under solar light irradiation. Therefore, the BiVO4 can be regarded as potential photocatalyst for degradation of industrial waste which is highly needed.

Heavy metal contamination harms soil and plant growth, making it a serious global environmental issue. Due to the scarcity of canal water, people have become more reliant on groundwater, but aquifers are expensive and of poor quality. Therefore, wastewater has become one of the essential sources of irrigation in developing countries and rural areas. In rural areas, sanitary, sewage, and municipal wastewater are the most common sources of irrigation. The objective was to analyze and compare the concentration of heavy metals in Spinach (Spinacia oleracea) collected from two different sites, i.e., one field irrigated using sanitary wastewater and another by tube well water through drainage ditches in a rural area of Faisalabad. AAS (Atomic Absorption Spectrophotometry) analyzed heavy metals from plants through irrigated water, soil, and the collected edible parts of plant samples. The samples were digested by using acids and AAS-analyzed metals. The concentration of Cd (0.051 ± 0.029) mg/l found higher than the recommended values by WHO (0.01 mg/l) in sanitary wastewater, as well as Cd concentration (0.478 ± 0.276) mg/kg in edible parts of spinach, also detected beyond the permissible limits (0.2) mg/kg of WHO (2007). These exceeding values of Cd in edible parts of spinach may cause serious human health risks.

Abstract Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4–5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.

Background Merkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (~80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens.Methods A patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy. She received anti-PD-L1 (avelumab) and had a partial response within 4 weeks. Whole exome sequencing (WES) was performed to determine potential neoantigen peptides. Characterization of peripheral blood neoantigen T cell responses was evaluated via interferon-gamma (IFNγ) ELISpot, flow cytometry and single-cell RNA sequencing. Tumor-resident T cells were characterized by multiplexed immunohistochemistry.Results WES identified 1027 tumor-specific somatic mutations, similar to the published average of 1121 for VN-MCCs. Peptide prediction with a binding cut-off of ≤100 nM resulted in 77 peptides that were synthesized for T cell assays. Although peptides were predicted based on class I HLAs, we identified circulating CD4 T cells targeting 5 of 77 neoantigens. In contrast, no neoantigen-specific CD8 T cell responses were detected. Neoantigen-specific CD4 T cells were undetectable in blood before anti-PD-L1 therapy but became readily detectible shortly after starting therapy. T cells produced robust IFNγ when stimulated by neoantigen (mutant) peptides but not by the normal (wild-type) peptides. Single cell RNAseq showed neoantigen-reactive T cells expressed the Th1-associated transcription factor (T-bet) and associated cytokines. These CD4 T cells did not significantly exhibit cytotoxicity or non-Th1 markers. Within the pretreatment tumor, resident CD4 T cells were also Th1-skewed and expressed T-bet.Conclusions We identified and characterized tumor-specific Th1-skewed CD4 T cells targeting multiple neoantigens in a patient who experienced a profound and durable partial response to anti-PD-L1 therapy. To our knowledge, this is the first report of neoantigen-specific T cell responses in MCC. Although CD4 and CD8 T cells recognizing viral tumor antigens are often detectible in virus-positive MCC, only CD4 T cells recognizing neoantigens were detected in this patient. These findings suggest that CD4 T cells can play an important role in the response to anti-PD-(L)1 therapy.

Abstract Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ablation of either Palb2 or Brca2 with Brca1 led to delayed tumor formation. Whole-exome sequencing (WES) revealed both similarities and differences between Brca1 and Palb2 or Brca2 null tumors. Analyses of mouse mammary glands and cultured human cells showed that combined loss of BRCA1 and PALB2 led to high levels of reactive oxygen species (ROS) and increased apoptosis, implicating oxidative stress in the delayed tumor development in Brca1;Palb2 double CKO mice. The functional complementarity between BRCA1 and PALB2/BRCA2 and the role of ROS in tumorigenesis require further investigation.

Abstract Metaplastic breast cancers (MBCs) are characterized by complex genomes, which seem to vary according to their histologic subtype. TERT promoter hotspot mutations and gene amplification are rare in common forms of breast cancer, but present in a subset of phyllodes tumors. Here, we sought to determine the frequency of genetic alterations affecting TERT in a cohort of 60 MBCs with distinct predominant metaplastic components (squamous, 23%; spindle, 27%; osseous, 8%; chondroid, 42%), and to compare the repertoire of genetic alterations of MBCs according to the presence of TERT promoter hotspot mutations or gene amplification. Forty-four MBCs were subjected to: whole-exome sequencing (WES; n = 27) or targeted sequencing of 341-468 cancer-related genes (n = 17); 16 MBCs were subjected to Sanger sequencing of the TERT promoter, TP53 and selected exons of PIK3CA, HRAS, and BRAF. TERT promoter hotspot mutations (n = 9) and TERT gene amplification (n = 1) were found in 10 of the 60 MBCs analyzed, respectively. These TERT alterations were less frequently found in MBCs with predominant chondroid differentiation than in other MBC subtypes (p = 0.01, Fisher’s exact test) and were mutually exclusive with TP53 mutations (p

There is an unmet clinical need for simple, accessible biomarkers to select patients who are more likely to respond to immune checkpoint therapy. Here the authors show that a lower neutrophil-to-lymphocyte ratio is associated with better overall and progressive-free survival, as well as higher rate of response, in a multi-cancer cohort of patients treated with immune checkpoint inhibitors.

Polyethylene microplastic (PE-MP) is amongst the most manufactured plastics globally. However, emerging studies report its adverse effects on wildlife and humans. Luteolin (LUT) is a flavonoid compound known for its potent antioxidant properties. The present study was designed to estimate the toxic effect of PE-MP on testicles of adult male rats. The therapeutic potential of LUT was also determined in alleviating PE-MP instigated testicular dysfunctions. An experiment was carried on 48 adult male Sprague-Dawley rats, which were randomly classified into four groups: control, PE-MP (1.5 mg/kg), PE-MP + LUT (1.5 mg/kg + 50 mg/kg respectively), and LUT (50 mg/kg). The biochemical, spermatogenic, hormonal, and histopathological parameters were studied after 56 days of treatment. PE-MP exposure disrupted the biochemical profile by reducing catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GSR) activities. In comparison, the concentration of reactive oxygen species (ROS) and malondialdehyde (MDA) levels were increased. PE-MP-intoxication also reduced the sperm motility, viability, the number of hypo-osmotic tails swelled spermatozoa, and epididymal sperm count; additionally, it increased the sperm morphological (head–tail and mid-piece) abnormalities. Furthermore, it lowered luteinizing hormone (LH), follicle-stimulating hormone (FSH), and plasma testosterone. PE-MP exposure led to histopathological damages in testicular tissues. However, LUT inverted all the illustrated impairments in testes. Our results demonstrate that PE-MP could cause testicular damage in male rats, effectively mitigated by LUT treatment.

Purpose: Radiation treatment plans undergo peer review during chart rounds, but changes to treatment volumes would require replanning. Our group implemented weekly head and neck cancer “volume rounds” to peer review all target volumes for head and neck cancer before radiation therapy (RT) planning and chart rounds. Methods and Materials: We analyzed modifications made to planning target volumes (PTVs) at volume rounds for consecutive nonproton head and neck cancer cases from May 2020 to May 2021. Nine head and neck radiation oncologists participated in weekly volume rounds during this time. Recommendations were categorized as no changes, minor changes, major changes, additional workup (eg, biopsy or imaging), and consultation or tumor board discussion needed before the start of RT. Minor changes to PTVs generally did not require a second review before treatment planning while major changes did. Results: PTVs for 511 cases involving 432 patients underwent peer review and 298 (58.3%) of these cases did not require any modifications before treatment planning. Minor and major changes were recommended in 75 (14.7%) and 86 (16.8%) cases, respectively. Forty-five (8.8%) cases were recommended to have additional workup and 23 (4.5%) required additional consultation with nonradiation surgeons or medical oncologists. Of the 45 cases that were recommended for additional workup, 40 underwent biopsy or imaging. Positive findings on imaging or biopsy occurred in 13 patients, leading to a significant change in management, including 4 patients who underwent additional surgery after positive findings before the start of RT. Conclusions: Prospective peer review during head and neck cancer volume rounds led to frequent minor and major alterations to PTVs. Significant changes in the overall treatment plan, such as additional surgery before start of RT, occurred in a minority of patients.

Purpose: Recurrent head and neck cancers are associated with significant morbidity and mortality. Outcomes of multiple courses of radiation have not yet been described. Methods and Materials: A single institution database was queried to retrospectively review treatment plans and select patients who underwent ≥ 3 courses of radiation to the head and neck region. Results: Thirty-three patients were found to have ≥ 3 courses of radiation with overlapping fields. Median local recurrence free survival after last course of reirradiation was 9.1 months and median overall survival was 10 months. Grade 3 and above toxicities were reported in 15 patients (45%). Grade 4 and above toxicities were reported in seven patients (21%). There was no grade 5 toxicity. 20 patients (61%) underwent subsequent therapies following completion of repeat reirradiation. Conclusions: Repeat reirradiation to the head and neck region is feasible and carries significant risks that are most appropriately managed with a multi-disciplinary team and must be balanced against the potential for local control and opportunities for emerging systemic therapies.

Purpose: To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base. Materials and Methods: Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with < 3 months of follow-up, receiving < 45GyRBE or nonconventional fractionation, and/or no follow-up magnetic resonance imaging (MRI) were excluded. TLN was determined using MRI and graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Clinical (gender, age, comorbidities, concurrentchemotherapy, smoking, radiation techniques) and dose-volume parameters were analyzed for TLN correlation. The receiver operating characteristic curve and area under the curve (AUC) were performed to determine the cutoff points of significant dose-volume parameters. Results: Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range =3.2–69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N =13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporallobe; and dose to the 0.5, 1, and 2 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 showed maximum specificity and sensitivity. Conclusion: The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm3, D2cm3 ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.

In recent years, polypropylene microplastic has persisted in freshwater ecosystems and biota, forming ever-growing threats. This research aimed to prepare polypropylene microplastics and evaluate their toxicity to the filter feeder Oreochromis mossambicus. In this research, fish were given a dietary supplement of polypropylene microplastics at 100, 500, and 1000 mg/kg for acute (96 h) and sub-acute (14 days) durations to assess toxic effects on liver tissues. FTIR results revealed the presence of polypropylene microplastic in their digestion matter. The ingestion of microplastics in O. mossambicus led to fluctuations in homeostasis, an upsurge in reactive oxygen species (ROS) levels, an alteration in antioxidant parameters, including superoxide dismutase (SOD), catalase (CAT), glutathione-S–transferase (GST), and glutathione peroxidase (GPx); a promotion in the oxidation of lipid molecules; and a denaturation in the neurotransmitter enzyme acetylcholinesterase (AChE). Our data indicated that sustained exposure to microplastics (14 days) produced a more severe threat than acute exposure (96 h). In addition, higher apoptosis, DNA damage (genotoxicity), and histological changes were found in the liver tissues of the sub-acute (14 days) microplastics-treated groups. This research indicated that the constant ingestion of polypropylene microplastics is detrimental to freshwater environments and leads to ecological threats.

Mangrove forest is one of the productive ecosystems that provide essential habitats for various fauna as breeding and feeding drives. However, heavy metal pollution in the mangrove forest has led to severe health problems for several aquatic species. Biomonitoring of metals using a nondestructive method is an emerging technique. Scats of the fishing cat (Prionailurus viverrinus) were collected from five locations in the Godavari estuary mangrove habitats, Coringa Wildlife Sanctuary, Andhra Pradesh, India, to determine the level of various metals. An opportunistic method was applied to collect scats in the mangrove forest. Six scat samples were collected from each of the sampling sites. The following prey species, such as crabs, fishes, birds, rodents, plants, plastics, and unidentifiable prey matters, were found in the scats. Select metals, such as chromium (Cr), copper (Cu), and lead (Pb) were analyzed from the scats of the fishing cat since they intensively influence the physiology and behavior of top predators. The concentration of Cu in fishing cat scats was higher than the other two metals assessed. Metals showed statistically substantial variation across locations (p < 0.05). According to the current study, heavy metals may significantly threaten the fishing cat in the Coringa Wildlife Sanctuary. The fishing cat is a vulnerable species in accordance with the ICUN categories. Due to pollution and other human pressures, the fishing cat may soon be categorized as a threatened or endangered species; the research advises that authorities should prioritize the protection of the vulnerable species of the fishing cat from the Coringa Wildlife Sanctuary, Andhra Pradesh, India.

Heavy metal discharge is the primary cause of freshwater pollution, harming fish health. This research was planned to calculate the seasonal variations in metal (Pb, Cu, and Ni) bioaccumulation in different tissues of Gills, Liver, Kidney, and Muscle from Cirrhinus mrigala sampled from River Chenab from an area of high-intensity pollution near Thatta Muhammad Shah. The results revealed significant (P ≤ 0.5) variations in metals bioaccumulation in different seasons. The lowest level of selected metals was observed in winter, whereas the maximum level was noted in the summer. The concentration of selected heavy metals differed seasonally. During winter Pb concentration distribution in descending order was observed in liver (0.823 ± 0.009 ppm) > kidney(0.817 ± 0.011 ppm) > muscle(0.758 ± 0.009 ppm) > gills(0.742 ± 0.011 ppm). Whereas, in summer it was noted as liver (1.726 ± 0.066 ppm) > gills (1.633 ± 0.060 ppm) > kidney (1.575 ± 0.051 ppm) > muscle (1.532 ± 0.050 ppm). While during winter, the bioaccumulation of Cu in organs was noted with descending order of kidney (1.88 ± 0.038) > liver(1.75 ± 0.037) > gills (1.67 ± 0.043) > muscle (1.45 ± 0.031)ppm, while in summer, it was gills (2.85 ± 0.071) > kidney (2.84 ± 0.082) > liver (2.83 ± 0.068) > muscle (2.72 ± 0.065) ppm. In winter, the Ni bioaccumulation with descending order was in the kidney (7.83 ± 0.139) > liver (7.68 ± 0.159) > muscle (7.63 ± 0.162) > gills (7.61 ± 0.129)ppm and in a season of summer, it was detected as in kidney (8.71 ± 0.129) > muscle (8.59 ± 0.131) > liver (8.56 ± 0.141) > gills (8.56 ± 0.131) ppm. All studied heavy metals were found to be above the WHO permissible limits. Histopathological evaluation of fish tissues has been considered an important indicator of environmental pollution monitoring. Histology of kidney and liver tissues showed congestion, necrosis, dilation in Bowman capsule space, while liver showed necrosis, cytoplasmic vacuolation, and sinusoid dilation. This study revealed that the Chenab River is being polluted due to the untreated discharge of industrial effluents and sewage runoff from the city, and these heavy metals from anthropogenic pollution load have adverse effects on the fish population in the river system.

Cisplatin (CP) is one of the most effective chemotherapeutic drugs used to treat different tumors. Vitexin (VIT) is a natural flavonoid having various pharmacological activities along with its curative effects. The present research was planned to evaluate the therapeutic potential of VIT on cisplatin-induced renal damage in male albino rats. Twenty-four male albino rats were divided into four equal groups. These groups were treated with CP (10 mg/kg injection on the first day of trial) administered group, cotreated (CP; 10 mg/kg + VIT; 10 mg/kg) and only VIT (10 mg/kg orally till the end of the trial) treated group and a control. CP administration significantly decreased the activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione S-transferase (GST), glutathione (GSH), and glutathione reductase (GSR). The levels of thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H2O2) were increased. CP-treatment significantly increased the levels of urea, creatinine, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) while considerably reducing the creatinine clearance. The results demonstrated that CP significantly increased the inflammation markers, including tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activities and histopathological damages. However, co-treatment with VIT efficiently minimized the CP-induced biochemical, inflammatory, and histopathological impairments in rat kidneys. The study's outcomes indicated the significant curative efficacy of VIT to overcome CP-induced nephrotoxicity in male albino rats.

Abstract The present research was planned to analyze the toxic effects of thimerosal on rat liver. Mercury and mercury compounds are universally known toxicants for animals and humans. Thimerosal is widely used in the vaccines as a preservative which contains 49.6% mercury. Twenty-four adult male albino rats were distributed into four groups (n=6). The first group was considered as a control group. While, second, third and fourth groups were intoxicated with 0.5, 10 and 50 µg/kg thimerosal (i.m.) respectively. After 30 days, rats were slaughtered to analyze the liver tissues. The results of the experiment exposed that thimerosal instigated significant (p

Arsenic (As) is a toxic contaminant present in organic and inorganic forms in the environment. Nobiletin (NOB) is a polymethoxy flavone that has recently gained substantial consideration due to its curative impacts. The present experiment was conducted to assess the hepatoprotective efficiency of NOB on As-generated hepatotoxicity. Twenty-four adult rats were equally distributed into four groups and designated as control, As (50 mg/kg)-treated, As + NOB (50 mg/kg and 25 mg/kg, respectively), and NOB (25 mg/kg)-treated groups. After 30 days, experimental animals were decapitated, then blood and tissue samples were collected for further analysis. The group treated with As showed a significant decrease in the activity of antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione (GSH), glutathione reductase (GSR), and total antioxidant status (TAS), and a substantial increase in the accumulation of As in liver tissues, levels of total oxidant status (TOS), hydrogen peroxide (H2O2), and lipid peroxidation (TBARS). Significant increases in alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) levels were observed in As-treated rats. Moreover, nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interleukin (IL)-6, and cyclo-oxygenase (COX)-2 activity, as well as the levels of pro-apoptotic markers (Bax, Caspase-3, and Caspase-9) were increased on exposure to As. In contrast, the anti-apoptotic marker (Bcl-2) level was significantly decreased. As administration showed a significant disturbance in hepatic tissue histology. However, cotreatment of NOB with As considerably increased the antioxidant enzyme activity, with a noteworthy reduction in the deposition of As in hepatic tissues, TBARS, and H2O2 levels. NOB-administrated rats showed considerable recovery in terms of inflammation, apoptosis, and histological damage. Hence, NOB can be considered a useful curative compound due to its medicinal properties against As-prompted hepatotoxicity.