Recent trends in polycyclic aromatic hydrocarbons pollution distribution and counteracting bio-remediation strategies.

Polycyclic aromatic hydrocarbons (PAHs) are distributed worldwide due to long-term anthropogenic pollution sources. PAHs are recalcitrant and highly persistent in the environment due to their inherent properties, such as heterocyclic aromatic ring structures, thermostability, and hydrophobicity. They are highly toxic, carcinogenic, immunotoxic, teratogenic, and mutagenic to various life systems. This review focuses on the unique data of PAH sources, exposure routes, detection techniques, and harmful effects on the environment and human health. This review provides a comprehensive and systematic compilation of eco-friendly biological treatment solutions for PAH remediation, such as microbial remediation approaches utilizing microbial cultures. In situ and Ex situ bioremediation of PAH methods, including composting land farming, biopiles, bioreactors bioaugmentation, and phytoremediation processes, are discussed in detail, as is a summary of the factors affecting and limiting PAH bioremediation. This review provides an overview of emerging technologies that use multi-process combinatorial treatment approaches and answers to generating value-added by-products during PAH remediation.

Implications of reactive oxygen species in lung cancer and exploiting it for therapeutic interventions.

Lung cancer is the second (11.4%) most commonly diagnosed cancer and the first (18%) to cause cancer-related deaths worldwide. The incidence of lung cancer varies significantly among men, women, and high and low-middle-income countries. Air pollution, inhalable agents, and tobacco smoking are a few of the critical factors that determine lung cancer incidence and mortality worldwide. Reactive oxygen species are known factors of lung carcinogenesis resulting from the xenobiotics and their mechanistic paths are under critical investigation. Reactive oxygen species exhibit dual roles in cells, as a tumorigenic and anti-proliferative factor, depending on spatiotemporal context. During the precancerous state, ROS promotes cancer origination through oxidative stress and base-pair substitution mutations in pro-oncogenes and tumor suppressor genes. At later stages of tumor progression, they help the cancer cells in invasion, and metastases by activating the NF-kB and MAPK pathways. However, at advanced stages, when ROS exceeds the threshold, it promotes cell cycle arrest and induces apoptosis in cancer cells. ROS activates extrinsic apoptosis through death receptors and intrinsic apoptosis through mitochondrial pathways. Moreover, ROS upregulates the expression of beclin-1 which is a critical component to initiate autophagy, another form of programmed cell death. ROS is additionally involved in an intermediatory step in necroptosis, which catalyzes and accelerates this form of cell death. Various therapeutic interventions have been attempted to exploit this cytotoxic potential of ROS to treat different cancers. Growing body of evidence suggests that ROS is also associated with chemoresistance and cancer cell immunity. Considering the multiple roles of ROS, this review highlights the exploitation of ROS for various therapeutic interventions. However, there are still gaps in the literature on the dual roles of ROS and the involvement of ROS in cancer cell immunity and therapy resistance.

Strongylopus grayii tadpole blastema extract exerts cytotoxic effects on embryonal rhabdomyosarcoma cells.

Amphibians have regenerative capacity and are resistant to developing cancer. This suggests that the developing blastema, located at the tissue regeneration site, may secrete anti-cancer factors. Here, we investigate the anti-cancer potential of tadpole tail blastema extracts (TAD) from the stream frog, Strongylopus grayii, in embryonal rhabdomyosarcoma (ERMS) cells. ERMS originates in skeletal muscle tissue and is a common pediatric soft tissue sarcoma. We show using MTT assays that TAD inhibited ERMS cell viability in a concentration-dependent manner, and phase contrast/fluorescent microscopy revealed that it induced morphological markers of senescence and apoptosis. Western blotting showed that this was associated with DNA damage (γH2AX) and activation of the p38/MAPK stress signaling pathway as well as molecular markers of senescence (p16INK4a), apoptosis (cleaved PARP), and inhibition of cell cycle promoters (cyclin A, CDK2, and cyclin B1). Furthermore, proteomics followed by gene ontology analyses showed that TAD treatment inhibited known tumor promoters and proteins required for cancer cell survival. Lastly, using the LINCS drug perturbation library, we show that there is an overlap between the proteomics signature induced by TAD and common anti-cancer drugs. Taken together, this study provides novel evidence that TAD exhibits cytotoxicity in ERMS cells.

The palladacycle, BTC2, exhibits anti-breast cancer and breast cancer stem cell activity.

In women globally, breast cancer is responsible for most cancer-related deaths and thus, new effective therapeutic strategies are required to treat this malignancy. Platinum-based compounds like cisplatin are widely used to treat breast cancer, however, they come with limitations such as poor solubility, adverse effects, and drug resistance. To overcome these limitations, complexes containing other platinum group metals such as palladium have been studied and some have already entered clinical trials. Here we investigated the anti-cancer activity of a palladium complex, BTC2, in MCF-7 oestrogen receptor positive (ER+) and MDA-MB-231 triple negative (TN) human breast cancer cells as well as in a human breast cancer xenograft chick embryo model. BTC2 exhibited an average IC50 value of 0.54 µM, a desirable selectivity index of >2, inhibited the migration of ER+ and TN breast cancer cells, and displayed anti-cancer stem cell activity. We demonstrate that BTC2 induced DNA double strand breaks (increased levels of γ-H2AX) and activated the p-ATM/p-CHK2 and p-p38/MAPK pathways resulting in S- and G2/M-phase cell cycle arrests. Importantly, BTC2 sensitised breast cancer cells by triggering the intrinsic (cleaved caspase 9) and extrinsic (cleaved caspase 8) apoptotic as well as necroptotic (p-RIP3 and p-MLKL) cell death pathways and inhibiting autophagy and its pro-survival role. Furthermore, in the xenograft in vivo model, BTC2 displayed limited toxicity and arrested the tumour growth of breast cancer cells over a 9-day period in a manner comparable to that of the positive control drug, paclitaxel. BTC2 thus displayed promising anti-breast cancer activity.

Galenia africana plant extract exhibits cytotoxicity in breast cancer cells by inducing multiple programmed cell death pathways.

Globally, breast cancer is the most common malignancy in women and the second most common cause of cancer-related death among women. There is therefore a need to identify more efficacious therapies for this neoplasm. Galenia africana (Kraalbos) is a perennial shrub found in Southern Africa and is used by the indigenous people to treat various ailments. There has therefore been much interest to establish the scientific basis for the medicinal properties of Kraalbos. This study aimed to investigate and characterise the anti-cancer activity of an ethanolic extract of Kraalbos leaves, KB2, against oestrogen receptor positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. LC-MS/MS analyses identified the phytochemicals 7'-hydroxyflavanone, 5',7'-dihydroxyflavanone, 2',4'-dihydroxydihydrochalcone and 2',4'-dihydroxychalcone in KB2. KB2 exhibited an IC50 of 114 µg/ml and 130.5 µg/ml in MCF-7 and MDA-MB-231 cells respectively, selectively inhibited their long-term survival and reduced their migration which correlated with a decrease in EMT markers. It induced oxidative stress (ROS), DNA damage (increased levels of γ-H2AX), and triggered cell cycle arrests in MCF-7 and MDA-MB-231 cells. Importantly, KB2 activated intrinsic (cleaved caspase 9) and extrinsic (cleaved caspase 8) apoptosis, necroptosis (p-RIP3 and the downstream target of the necrosome, pMLKL) and autophagy (LC3II). Co-treatment of the breast cancer cells with KB2 and the autophagy inhibitor bafilomycin A1 resulted in a significant increase in cell viability which suggests that KB2 induced autophagy is a cell death mechanism.

The roles and regulation of TBX3 in development and disease.

TBX3, a member of the ancient and evolutionary conserved T-box transcription factor family, is a critical developmental regulator of several structures including the heart, mammary glands, limbs and lungs. Indeed, mutations in the human TBX3 lead to ulnar mammary syndrome which is characterized by several clinical malformations including hypoplasia of the mammary and apocrine glands, defects of the upper limb, areola, dental structures, heart and genitalia. In contrast, TBX3 has no known function in adult tissues but is frequently overexpressed in a wide range of epithelial and mesenchymal derived cancers. This overexpression greatly impacts several hallmarks of cancer including bypass of senescence, apoptosis and anoikis, promotion of proliferation, tumour formation, angiogenesis, invasion and metastatic capabilities as well as cancer stem cell expansion. The debilitating consequences of having too little or too much TBX3 suggest that its expression levels need to be tightly regulated. While we have a reasonable understanding of the mutations that result in low levels of functional TBX3 during development, very little is known about the factors responsible for the overexpression of TBX3 in cancer. Furthermore, given the plethora of oncogenic processes that TBX3 impacts, it must be regulating several target genes but to date only a few have been identified and characterised. Interestingly, while there is compelling evidence to support oncogenic roles for TBX3, a few studies have indicated that it may also have tumour suppressor functions in certain contexts. Together, the diverse functional elasticity of TBX3 in development and cancer is thought to involve, in part, the protein partners that it interacts with and this area of research has recently received some attention. This review provides an insight into the significance of TBX3 in development and cancer and identifies research gaps that need to be explored to shed more light on this transcription factor.

Genetic spectrum of low density lipoprotein receptor gene variations in South Indian population.

BACKGROUND: Low density lipoprotein receptor (LDLR) is a membrane bound receptor maintaining cholesterol homeostasis along with Apolipoprotein B (APOB), Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and other genes of lipid metabolism. Any pathogenic variation in these genes alters the function of the receptor and leads to Familial Hypercholesterolemia (FH) and other cardiovascular diseases. OBJECTIVE: This study was aimed at screening the LDLR, APOB and PCSK9 genes in Hypercholesterolemic patients to define the genetic spectrum of FH in Indian population. METHODS: Familial Hypercholesterolemia patients (n=78) of South Indian Tamil population with LDL cholesterol and Total cholesterol levels above 4.9mmol/l and 7.5mmol/l with family history of Myocardial infarction were involved. DNA was isolated by organic extraction method from blood samples and LDLR, APOB and PCSK9 gene exons were amplified using primers that cover exon-intron boundaries. The amplicons were screened using High Resolution Melt (HRM) Analysis and the screened samples were sequenced after purification. RESULTS: This study reports 20 variations in South Indian population for the first time. In this set of variations 9 are novel variations which are reported for the first time, 11 were reported in other studies also. The in silico analysis for all the variations detected in this study were done to predict the probabilistic effect in pathogenicity of FH. CONCLUSION: This study adds 9 novel variations and 11 recurrent variations to the spectrum of LDLR gene mutations in Indian population. All these variations are reported for the first time in Indian population. This spectrum of variations was different from the variations of previous Indian reports.

Genotoxicity evaluation of metformin and glimepiride by micronucleus assay in exfoliated urothelial cells of type 2 diabetes mellitus patients.

Micronucleus (MN) assay was performed on the exfoliated urothelial cells to detect the genotoxic effects of the anti-hyperglycemic drugs, metformin and glimepiride in T2DM patients and to use it as a biomarker for DNA damage by assessing the frequency of micronuclei in the exfoliated urothelial cells. A total of 201 subjects (147 T2DM patients & 54 Normal cases) were selected from diverse age groups (25-75 years) and the mean MN frequency was examined per 1000 cells in all the subjects. Relative to the control group (5.02 ± 1.01), an increased MN frequency was observed in females (26.15 ± 2.15) when compared to males (23.08 ± 2.09) in T2DM patients. Further analysis showed that there was a profound increase in the number of MN in the patients using metformin alone (23.02 ± 4.44), or combination of metformin & glimepiride (24.98 ± 2.87) than to the subjects using glimepiride alone (17.52 ± 3.28). It has been proven by this simple, reliable and non-invasive method that metformin has a potential role in causing genotoxicity and that the MN observed in exfoliated urothelial cells could be used as a reliable biomarker in monitoring the genotoxic risk of the anti-hyperglycemic drugs.