Molecular pathways and therapeutic targets linked to triple-negative breast cancer (TNBC).

Cancer is a group of diseases characterized by uncontrolled cellular growth, abnormal morphology, and altered proliferation. Cancerous cells lose their ability to act as anchors, allowing them to spread throughout the body and infiltrate nearby cells, tissues, and organs. If these cells are not identified and treated promptly, they will likely spread. Around 70% of female breast cancers are caused by a mutation in the BRCA gene, specifically BRCA1. The absence of progesterone, oestrogen and HER2 receptors (human epidermal growth factor) distinguishes the TNBC subtype of breast cancer. There were approximately 6,85,000 deaths worldwide and 2.3 million new breast cancer cases in women in 2020. Breast cancer is the most common cancer globally, affecting 7.8 million people at the end of 2020. Compared to other cancer types, breast cancer causes more women to lose disability-adjusted life years (DALYs). Worldwide, women can develop breast cancer at any age after puberty, but rates increase with age. The maintenance of mammary stem cell stemness is disrupted in TNBC, governed by signalling cascades controlling healthy mammary gland growth and development. Interpreting these essential cascades may facilitate an in-depth understanding of TNBC cancer and the search for an appropriate therapeutic target. Its treatment remains challenging because it lacks specific receptors, which renders hormone therapy and medications ineffective. In addition to radiotherapy, numerous recognized chemotherapeutic medicines are available as inhibitors of signalling pathways, while others are currently undergoing clinical trials. This article summarizes the vital druggable targets, therapeutic approaches, and strategies associated with TNBC.

Heavy metal-induced genotoxic, physiological, and biochemical responses in Schizothorax esocinus (Heckel 1838) inhabiting the Dal Lake, India, and phytoremediation by indwelling plants.

Heavy metals have an immense impact on aquatic ecosystems, and their toxic effects are transferred to the inhabiting organisms. Experiments were conducted to investigate the health of snow trout Schizothorax esocinus inhabiting Dal Lake. Heavy metals (Cd > Ni > Cu > Cr) were found to accumulate in the major immune organs of the fish (head kidney, liver, spleen, thymus) which led to change in the overall physiology. The head kidney, liver, and spleen of a fish contain high amount of these metals. The least accumulation of these metals was found in the blood, whereas Cd and Ni were completely absent in the integument. Hepatic marker enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)) were normal, while the renal marker enzyme creatine kinase showed marked difference in its value. The cortisol level was normal, while immunoglobulin M showed elevated level representing active immunity. At a cellular level, the histopathology of immune organs showed marked damage. Metallothionein (MT) and glutathione peroxidase (GPX) genes showed variable expression pattern in the immune organs with the head kidney showing the highest expression of both the genes, and blood showed the least. We observed that the aquatic plants (Nelumbo nucifera and Trapa natans) inhabiting the lake played an important role in phytoremediation. An integrated approach involving biochemical, hematological, genotoxic, and histopathological studies can provide a valuable information to understand fish adaptive patterns and monitor water quality.

Biochemical profile and gene expression of Clarias gariepinus as a signature of heavy metal stress.

Heavy metals have been found in increasing concentrations in the aquatic environment. Fishes exposed to such metals have altered gene expression, serum profiles, tissue histology and bioindices that serve as overall health biomarkers. The heavy metals (Ni, Cd, and Cr) accumulated in water and fish tissues, were beyond the permissible limits defined by the Central Pollution Control Board/World Health Organization. Metallothionein (MT) and glutathione peroxidase (GPX) genes expression patterns highlighted the metal-specific exposure of fish. An increased fold change of genes against beta-actin serves as a potential feature for toxicity. Metal toxicity is also reflected by an increased level of digestive enzymes (amylase and lipase) in the serum and alterations in values of reproductive hormones (11-Ketotestosterone and progesterone). Total serum bilirubin attribute to the liver and biliary tract disease in fishes. Histopathological studies show cellular degeneration, breakage, vacuolization signifying the chronic stress.

Heavy metal toxicity has an immunomodulatory effect on metallothionein and glutathione peroxidase gene expression in Cyprinus carpio inhabiting a wetland lake and a culture pond.

The study provides cumulative data on the status of the two water bodies. The study designed revealed physicochemical properties (temperature, dissolved oxygen, pH, total dissolved solids and conductivity) to be in the desirable range, however, amongst the heavy metals excepting for Cd all were found to be higher than the permissible limits set by WHO and USEPA. It was observed that these elements cast their impact on bioindices (hepatosomatic index, condition factor, spleenosomatic index and kidney somatic index), renal marker enzyme (creatine kinase), hepatic marker enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase), histology of immune organs (liver, spleen, head-kidney and thymus) and level of serum immunoglobulin (IgM). Further, expression levels of Metallothionein (MT) and Glutathione peroxidase (GPX) genes in immune-related tissues (liver, spleen, head-kidney, thymus and blood) observed indicates metal pollution and abiotic stresses. These alterations are reliable indicators of the cellular and humoral immune response in Cyprinus carpio.

Insights into the heavy metal-induced immunotoxic and genotoxic alterations as health indicators of Clarias gariepinus inhabiting a rivulet.

There is a dire need to assess the quality of fishes transported for human consumption as lately, their health is challenged because of anthropogenic activities. Heavy metals with a long environmental persistence are toxic to fishes and the humans. The study was conducted to evaluate the impact of heavy metals on Clarias gariepinus inhabiting popular Ganges rivulet at Narora (28.18° E, 78.39° N). The limnological values deviated from the international Standards (USEPA, WHO). Higher total dissolved solids (859 mg/L), total suspended solids (406 mg/L), low dissolved oxygen (5.60 mg/L), and pH (5.21) indicated the presence of contaminants. Heavy metals estimated followed the order Cd > Ni > Cu > Cr. Serum enzymes (hepatic and renal markers) viz., aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were higher than the normal, whereas, creatine kinase (CK) was considerably low in both male and female fish. Stress induced was marked by elevation in cortisol and glucose. This had its impact on hematological parameters as well, as a decline in Total leucocyte count (TLC) & mean corpuscular volume (MCV) and increase in Mean cell hemoglobin (MCH) was observed. Erythrocytes also showed altered morphology. Marked histopathological alterations were observed in all immune organs (head-kidney, liver, spleen, thymus). Oxidative stress induced by heavy metals leads to the production of metal scavenging protein metallothionein (MT) and glutathione peroxidase (GPX). Maximum fold change in metallothionein (MT) gene expression was observed in the liver, followed by spleen, thymus, blood, and head-kidney. Glutathione peroxidase (GPX) gene expression was highest in the liver, followed by thymus, spleen, blood, and head-kidney. The gene expression studies further validated the increased level of heavy metals as potent contaminants of water and the non-condusive abiotic factors.

Comparative study of biochemical, histological and molecular biomarkers of heavy metal contamination in Cyprinus carpio collected from warm-monomictic lake and government culture pond.

The study investigated the metallothionein (MT) and glutathione peroxidase (GPX) genes expression in freshwater fish Cyprinus carpio dwelling in Warm-monomictic Lake (Dal) and Government culture pond. Oxidative stress induced by heavy metals in the fish body manipulates stress genes expression resulting in the production of scavenger protein (for free metal ions) metallothionein. It interacts with Cu, Cr, Ni and Cd via metal-thiolate bond relieving the metal load from fish body. Maximum fold change was observed in liver, muscle and midgut tissue. Similar rise seen in GPX indicates defence against lipid peroxidation. MT and GPX genes data were compared with beta-actin gene used as an internal control. Limnological studies of both the sites (temperature, dissolved oxygen, pH, total dissolved solids, conductivity), were essential to ensure the quality of water in which the dominant species (C. carpio) was thriving, as these fishes are transported for human consumption. Heavy metal concentration (water, tissues, gut content), bioindices, biochemical parameters and histological alterations were studied to observe the impact of elements selected.

Publisher Correction: Multiple biomarker responses (serum biochemistry, oxidative stress, genotoxicity and histopathology) in Channa punctatus exposed to heavy metal loaded waste water.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Multiple biomarker responses (serum biochemistry, oxidative stress, genotoxicity and histopathology) in Channa punctatus exposed to heavy metal loaded waste water.

Experiments were conducted to investigate the health of fish Channa punctatus inhabiting heavy metal-loaded waste water. Heavy metals in the order of Fe > Mn > Zn > Co > Ni > Cu = Cr were present in the waste water. Gills had high metal load followed by liver and then kidney. Albumin, albumin to globulin (A:G) ratio, triglyceride, high density lipoprotein (HDL) and very low density lipoprotein (VLDL) were found to be lower but phospholipid, low density lipoprotein (LDL), total protein, lipid and cholesterol were higher as compared to the reference. Oxidative stress markers such as superoxide dismutase (SOD), catalase (CAT), glutathione S transferase (GST) and lipid peroxidation (LPO) were significantly higher in all tissues, whereas reduced glutathione (GSH) levels were comparatively low. Damage to DNA was observed with significantly higher mean tail length of comets in the exposed fish gill cells (30.9 µm) followed by liver (24.3 µm) and kidney (20.6 µm) as compared to reference fish (5.2, 4.8 and 5.9 µm respectively). Histopathology in gill, liver and kidney also showed marked damage. Integrated biochemical, oxidative stress, genotoxicity and histopathological findings are valuable biomarkers for native fish adaptive patterns, and monitoring of water quality/pollution of freshwater ecosystems.

Studies on the alterations in haematological indices, micronuclei induction and pathological marker enzyme activities in Channa punctatus (spotted snakehead) perciformes, channidae exposed to thermal power plant effluent.

The present study was conducted to assess the toxicity of thermal power plant effluent containing heavy metals (Fe > Cu > Zn > Mn > Ni > Co > Cr) on haematological indices, micronuclei, lobed nuclei and activity of pathological marker enzymes [alkaline phosphatase (ALP), aspartate transferase (AST), alanine transferase (ALT) and creatine kinase (CK)] in Channa punctatus. Total erythrocyte count (-54.52 %), hemoglobin (-36.98 %), packed cell volume (-36.25 %), mean corpuscular hemoglobin concentration (-1.41 %) and oxygen (O2) carrying capacity (-37.04 %) declined significantly over reference fish, however total leukocyte count (+25.43 %), mean corpuscular hemoglobin (+33.52 %) and mean corpuscular volume (+35.49 %) showed elevation. High frequency of micronuclei (1133.3 %) and lobed nuclei (150 %) were observed in exposed fish which may indicate mutagenesis. Activities of pathological marker enzymes ALP, AST, ALT and CK increased significantly in serum of exposed fish. The ratio of ALT: AST in exposed fish was beyond 1 which indicates manifestation of pathological processes. These biomarkers show that fish have macrocytic hypochromic anemia. Leukocytosis showed general defence response against heavy metal toxicity and marker enzymes showed tissue degeneration. In conclusion, thermal power plant effluent has strong potential to induce micronuclei, tissue pathology, making the fish anemic, weak, stressed and vulnerable to diseases.

Accumulation of heavy metals and human health risk assessment via the consumption of freshwater fish Mastacembelus armatus inhabiting, thermal power plant effluent loaded canal.

Bioaccumulation of six heavy metals (Mn, Fe, Co, Ni, Cu, Zn) in the muscle of highly consumed fish species (Mastacembelus armatus) were measured using atomic absorption spectrometer. Fe (213.29 mg/kg dry weight) concentration was the most, followed by Zn (186.19 mg/kg dry weight), Ni (58.98 mg/kg dry weight), Cu (41.36 mg/kg dry weight), Co (9.06 mg/kg dry weight) and Mn (9.03 mg/kg dry weight). Estimated daily intake of heavy metals was calculated by mean fish consumption rate 19.5 × 10(-3) kg/day, on the basis of a calculation of the amount of fish consumed by adult individuals (male and female). The studied fish species pose non carcinogenic risk for Co and Ni [target hazard quotient (THQ) > 1] only. Hazard index (HI) was high. Carcinogenic risk (TR) posed by this fish for male and female was 3.43 × 10(-3) and 3.91 × 10(-3), respectively for Ni (the carcinogenic potency slope factor was available for Ni only). The study is an alert indicating that inhabitants who consume these fishes (particularly females) were at risk of Co and Ni toxicity. In India recommended guidelines have yet not been established for these heavy metals, which is essential for setting of toxicological standards.

Studies on biomarkers of oxidative stress and associated genotoxicity and histopathology in Channa punctatus from heavy metal polluted canal.

Some investigations were made on the Satha canal water and health of dwelling fish Channa punctatus at Satha village, district Aligarh (U.P). Metal bioaccumulation and induction of biomarkers such as lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione S transferase (GST), reduced glutathione (GSH), DNA damage and histopathology are potential indicators of stress in C. punctatus exposed to effluents. In canal water Cr, Mn, Fe and Ni concentrations were exceeding the permissible limits set by both Bureau of Indian standards (BIS) and WHO. Fe (74%) was highly bioavailable and accumulated in all organs (gill, liver, kidney, muscle and integument). The highest metal pollution index (MPI) value of 53 was observed in gills and the lowest 6 in liver tissue. SOD and LPO were significantly higher in all tissues, whereas CAT, GST and GSH levels declined significantly compared to fish from the reference site. Concomitant damage to DNA was observed with significantly higher mean tail length in the exposed fish gill cells (19 µm) and in liver (12.7 µm) compared to reference fish (5 and 4 µm respectively). Histopathology in gill and liver also show significant damage. Therefore, it can be concluded that the sugar mill effluent has the potential to cause oxidative stress, DNA damage and histopathology in C. punctatus. This canal is a prime source of water and fish food to the local residents of the area. Therefore, the consumers may suffer adverse health effects like that in indicator organism.

Bioaccumulation, oxidative stress and genotoxicity in fish (Channa punctatus) exposed to a thermal power plant effluent.

Metal bioaccumulation and induction of biomarkers such as lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione S transferase (GST), reduced glutathione (GSH) and DNA damage are potential indicators of stress in Channa punctatus exposed to effluents. In canal water, receiving thermal power plant discharges, Fe and Ni concentrations exceeded the recommended guidelines set by the United Nations Environment Programme Global Environment Monitoring System (UNEPGEMS). Fe was highly bioavailable and accumulated in all organs (liver, kidney, muscle and integument). The highest metal pollution index (MPI) value of 41.2 was observed in kidney and the lowest 13.5 in muscle tissue. LPO, SOD, CAT and GST levels were significantly higher in liver and kidney, whereas GSH levels declined significantly compared to fish from the reference site. Concomitant damage to DNA was observed with significantly higher mean tail length in the exposed fish gill cells (26.5µm) and in liver (20.8µm) compared to reference fish. Therefore, it can be concluded that the thermal power plant effluent had the potential to cause oxidative stress and DNA damage in C. punctatus.

In vivo induction of antioxidant response and oxidative stress associated with genotoxicity and histopathological alteration in two commercial fish species due to heavy metals exposure in northern India (Kali) river.

Heavy metals can significantly bioaccumulate in fish tissues. The step wise mechanism of heavy metal toxicities on fish health is still limited. The present study assessed the tissue-specific antioxidant response and oxidative stress biomarkers of commercially important fish species namely, Channa striatus and Heteropneustes fossilis inhabiting Kali River of northern India where heavy-metal load is beyond the World Health Organisation - maximum permissible limits. Heavy metals chromium (Cr), nickel (Ni), lead (Pb) and cadmium (Cd) were elevated in both fish species compared to recommended values of the Federal Environmental Protection Agency (FEPA), 1999 for edible fishes. Reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CATA) activities in all tissues (brachial, neural, renal and hepatic) were altered. Cellular lipid and protein compromisation in both fishes induced by heavy metals was determined by lipid peroxidation (LPO) and protein carbonylation (PC) assays. Micronucleus (MN) test of erythrocytes and comet assay of liver cells confirmed genotoxicity. Histopathology of the liver, kidney and brain of affected fishes was distorted significantly with its reference fishes thereby affecting the quality and quantity of these fish stocks. This raises a serious concern as these fishes are consumed by the local population which would ultimately affect human health.

Stress response of biomolecules (carbohydrate, protein and lipid profiles) in fish Channa punctatus inhabiting river polluted by Thermal Power Plant effluent.

Qualitative and quantitative assessment of heavy metals in the Thermal Power Plant effluent was performed to study the impact of their toxic effects on various biomarkers (carbohydrate, protein and lipid profiles). Heavy metals present in the water were in the order Fe > Cu > Zn > Mn > Ni > Co > Cr. Fe and Ni exceeded and Cr was equal to the USA standards set by UNEPGEMS. Glycogen in liver (p < 0.001) and muscle (p < 0.01) depleted significantly. Insignificant (p < 0.05) decline in blood glucose (-21.0%) and significant (p < 0.05) elevation in both total protein and globulin in serum, liver and muscle was noted. Albumin decreased significantly (p < 0.01) in serum but showed significant (p < 0.05) increase in liver and muscle. Thus A:G ratio fell in serum and rose in liver and muscle. Similarly lipid profile also gets altered where significant elevation in serum total lipid (p < 0.01), total cholesterol (p < 0.01), phospholipid (p < 0.05), triglycerides (p < 0.001), LDL (p < 0.01) was observed but significant (p < 0.05) decline in VLDL was recorded. These biomarkers suggested that fish become hypoglycemic, hyperlipidemic and hypercholesterolemic. Heavy metals also provoked immune response as evident from the rise in globulin. In conclusion the Thermal Power Plant wastewater containing heavy metals induced stress, making fish weak and vulnerable to diseases.

Studies on the oxidative stress and gill histopathology in Channa punctatus of the canal receiving heavy metal-loaded effluent of Kasimpur Thermal Power Plant.

Some investigations were made on the canal water and inhabiting fish Channa punctatus at Kasimpur, district Aligarh (U.P.). It is a prime source for drinking, washing, and irrigation which was found to be receiving effluent from the adjoining Harduaganj Thermal Power Plant. The water samples were found to contain heavy metals, and the values obtained for Fe (8.71 mg L(-1)) and Ni (0.12 mg L(-1)) were beyond the recommended levels set by UNEPGEMS. C. punctatus was found to be the predominant fish in this canal. Fishes' gills are directly exposed to the ambience; hence, the changes are expected to be more prominent. Among the analyzed heavy metals, bioaccumulation of Zn (500.41 mg kg(-1) dry weight (dw)) was highest and Ni (13.93 mg kg(-1) dw), the least. Increased levels of lipid peroxidation (LPO) as well as antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione-S-transferase (GST) were found in the gills of the test fishes. The level of reduced glutathione (GSH), a nonenzymatic antioxidant, was quite expectedly lower than that in the reference fish. The gills of inhabiting fishes contained several lesions like necrosis, epithelial lifting, lamellar fusion, hyperplasia, syneching, infiltration of lymphocytes, and bridging in gill tissue. The present study demonstrated that wastewater/effluent released from thermal power plant containing heavy metals has strong potential to affect the physicochemical properties of the water and well-being of aquatic living organisms.

Assessment of genotoxic induction and deterioration of fish quality in commercial species due to heavy-metal exposure in an urban reservoir.

The aim of the study was to evaluate the effect of heavy-metal contamination on two fish species (Channa striatus and Heteropneustes fossilis) inhabiting a small freshwater body of northern India. After being captured, each specimen was weighed, measured, and analyzed for heavy metals (chromium [Cr], nickel [Ni], and lead [Pb]). Accumulation of heavy metals was found to be significantly greater (p < 0.05) in different tissues (gill, liver, kidney, and muscle) of fishes captured from the reservoir than from the reference site. Levels of heavy-metal contamination in Shah jamal water was Cr (1.51 mg/l) > Ni (1.22 mg/l) > Pb (0.38 mg/l), which is significantly greater than World Health Organization standards. Bioaccumulation factor was calculated, and it was observed that Pb was most detrimental heavy metal. Condition factor was also influenced. Micronucleus test of fish erythrocytes and comet assay of liver cells confirmed genotoxicity induced by heavy-metal contamination in fishes. Heavy metals (Cr, Ni, and Pb) were increased in both fish species as determined using recommended values of Federal Environmental Protection Agency for edible fishes. This raises a serious concern because these fishes are consumed by the local populations and hence would ultimately affect human health.

Assessment of heavy metal (Cu, Ni, Fe, Co, Mn, Cr, Zn) pollution in effluent dominated rivulet water and their effect on glycogen metabolism and histology of Mastacembelus armatus.

The present study was conducted to examine the contamination of rivulet situated at Kasimpur, Aligarh (27.218° N; 79.378° E). It receives the wastewater of Harduaganj Thermal Power Plant (HTPS) containing fly ash and heavy metals. Among the heavy metals estimated in the rivulet water, Fe (8.71 mgL(-1)) was present in the highest concentration followed by Cu (0.86 mgL(-1)), Zn (0.30 mgL(-1)) Mn (0.21 mgL(-1)), Ni (0.12 mgL(-1)), Co (0.11 mgL(-1)) and Cr (0.10 mgL(-1)). The values for the heavy metals such as Fe, Ni and Mn were beyond the limits set by UNEPGEMS. Bioaccumulation of these heavy metals was detected in tissues such as gills, liver, kidney, muscle and integument of the fish Mastacembelus armatus. Accumulation of Fe (213.29 - 2601.49 mgkg(-1).dw) was highest in all the organs. Liver was the most influenced organ and integument had the least metal load. The accumulation of Fe, Zn, Cu and Mn, observed in the tissues were above the values recommended by FAO/WHO. Biochemical estimation related to blood glucose, liver and muscle glycogen conducted showed significant (p < 0.01) elevation in blood glucose content over control (17.73%), whereas liver glycogen dropped significantly (p < 0.01) over control (-89.83%), and similarly muscle glycogen also decreased significantly (p < 0.05) over control (-71.95%), suggesting enhanced glycolytic capacity to fuel hepatic metabolism. Histopathological alterations were also observed in selected organs (gills, liver and kidney) of Mastacembelus armatus.

Histopathology and bioaccumulation of heavy metals (Cr, Ni and Pb) in fish (Channa striatus and Heteropneustes fossilis) tissue: a study for toxicity and ecological impacts.

Abstract: The water samples were collected from the 22 km segment III of Yamuna River from Okhla barrage. This segment receives water from 17 sewage drains of Delhi, Western Yamuna Canal (WYC), upper Ganga canal via Najafgarh drain and Hindon cut canal. Hence, the water samples collected were used to determine the presence of Chromium, Nickel and Lead through Atomic Absorption Spectrophotometry. The concentration of these heavy metals were much above the maximum permissible limits set by WHO. This was bound to have its influence on the riverine flora and fauna. To evaluate this, two popularly consumed fish species such as Channa striatus and Heteropneustes fossilis were caught and the bioaccumulation of these heavy metals were estimated in different organs (liver, kidney, gill and muscle). It was found that Cr accumulated the most in these organs (gill being most influenced) in both the species. The accumulation of all these heavy metals were above MPL set by World Health Organisation (WHO) and Food and Drug Administration (FDA). Histopathology was also conducted where heavy damages were observed in both liver and kidney of both the species.