Spatio-temporal variability in macroinvertebrate community structure and ecological health status of a tropical dynamic river-estuarine system, India: An integrated approach of multivariate analysis.

River-estuarine ecosystems are under severe anthropogenic threat due to resource exploitation, transportation, sewage/industrial discharges, and pollutants from surrounding areas. Monitoring the water quality and biological communities is essential for assessing ecosystem health and sustainability. Present study integrated the ecological community data along with water quality analysis to understand the impact of anthropogenic pressures on benthic macroinvertebrates. Samples were collected from 10 locations (comprising of both rural and urban areas) for Benthic macroinvertebrates, physico-chemical and microbiological parameters along the lower stretch of the Bhagirathi-Hooghly river-estuarine (BHE) system during the post-monsoon seasons of 2020, 2021, and 2022. During the entire study period, a total of 5730 individuals from 54 families in 19 orders of 3 phylum of macroinvertebrate were recorded. Among them Thiaridae (27.1%) and Chironomidae (22.8%) were found to be the most abundant families. Based on the water quality data Cluster analysis and nMDS indicated two distinct groups of locations: Group-I with rural settings and Group-II with urban settings. Alpha diversity metrics showed higher diversity (2.817) and evenness (0.744) in rural locations (Group-I) compared to urban locations (Group-II). The overall saprobic score of the macroinvebrate data revealed Group-I (5.09) to be in good condition, while Group-II (4.95) showed moderately polluted conditions. Redundancy analysis (RDA) highlighted the correlation of pollution-tolerant species (Chironomidae, Culicidae) with high organic loads i.e., biochemical oxygen demand (BOD), chemical oxygen demand (COD) in Group-II. In contrast, Group-I locations exhibited positive correlations with Dissolved Oxygen (DO) and supported less pollution-tolerant organisms (Coenagrionidae, Dytiscidae). The study emphasizes the importance of integrated analysis of ecological community data and water quality parameters to assess the health status of river-estuarine ecosystems.

Molecular and Cellular Factors Associated with Racial Disparity in Breast Cancer.

Recent studies have demonstrated that racial differences can influence breast cancer incidence and survival rate. African American (AA) women are at two to three fold higher risk for breast cancer than other ethnic groups. AA women with aggressive breast cancers show worse prognoses and higher mortality rates relative to Caucasian (CA) women. Over the last few years, effective treatment strategies have reduced mortality from breast cancer. Unfortunately, the breast cancer mortality rate among AA women remains higher compared to their CA counterparts. The focus of this review is to underscore the racial differences and differential regulation/expression of genetic signatures in CA and AA women with breast cancer. Moreover, immune cell infiltration significantly affects the clinical outcome of breast cancer. Here, we have reviewed recent findings on immune cell recruitment in the tumor microenvironment (TME) and documented its association with breast cancer racial disparity. In addition, we have extensively discussed the role of cytokines, chemokines, and other cell signaling molecules among AA and CA breast cancer patients. Furthermore, we have also reviewed the distinct genetic and epigenetic changes in AA and CA patients. Overall, this review article encompasses various molecular and cellular factors associated with breast cancer disparity that affects mortality and clinical outcome.

Novel combination of salinomycin and resveratrol synergistically enhances the anti-proliferative and pro-apoptotic effects on human breast cancer cells.

Resveratrol (RES) is a natural polyphenol having anti-proliferative activity against breast cancer cells. RES in combination with other chemo modulatory agents, minimizes toxicity and increases efficacy of the treatment. Salinomycin (SAL), a monocarboxylic polyether ionophore is known for selectively targeting breast cancer stem cells. Purpose of the present study was to investigate whether RES in combination with SAL exerts synergistic anti-proliferative activity on breast cancer cells. We further evaluated the molecular mechanism behind SAL and RES mediated cell death. Cytotoxicity assay was performed to determine 50% inhibitory concentration (IC50) of SAL and RES in different human breast cancer cells (HBCCs). Drug synergism and combination index (CI) were calculated using CompuSyn software and effects of synergistic combinations (CI < 1) involving lower doses of SAL and RES were selected for further studies. This combination significantly induced apoptosis in HBCCs without affecting non tumorigenic human breast epithelial cells MCF-10A. Co-treatment enhanced apoptosis in MCF-7 cells via reactive oxygen species (ROS) mediated mitochondrial dysfunction. Oxidative stress disrupt redox homeostasis which altered antioxidant enzymes viz. CuZn Superoxide dismutase (SOD), MnSOD and catalase. Additionally, combination altered nuclear morphology, enhanced PARP cleavage and led to caspase activation. SAL and RES also synergistically modulated MAPK pathway. Study suggests that SAL and RES offer a novel combination approach for the treatment of breast cancer.

Moxifloxacin-loaded nanoemulsions having tocopheryl succinate as the integral component improves pharmacokinetics and enhances survival in E. coli-induced complicated intra-abdominal infection.

In the present work, a novel nanoemulsion laden with moxifloxacin has been developed for effective management of complicated intra-abdominal infections. Moxifloxacin nanoemulsion fabricated using high pressure homogenization was evaluated for various pharmaceutical parameters, pharmacokinetics (PK) and pharmacodynamics (PD) in rats with E. coli-induced peritonitis and sepsis. The developed nanoemulsion MONe6 (size 168 ± 28 nm and zeta potential (ZP) 24.78 ± 0.45 mV, respectively) was effective for intracellular delivery and sustaining the release of MOX. MONe6 demonstrated improved plasma (AUC(MONe6/MOX) = 2.38-fold) and tissue pharmacokinetics of MOX (AUC(MONe6/MOX) = 2.63 and 1.47 times in lung and liver, respectively). Calculated PK/PD index correlated well with a reduction in bacterial burden in plasma as well as tissues. Enhanced survival on treatment with MONe6 (65.44%) and as compared to the control group (8.22%) was a result of reduction in lipid peroxidation, neutrophil migration, and cytokine levels (TNF-α and IL6) as compared to untreated groups in the rat model of E. coli-induced sepsis. Parenteral nanoemulsions of MOX hold a promising advantage in the therapy of E. coli-induced complicated intra-abdominal infections and is helpful in the prevention of further complications like septic shock and death.

Cannabidiol Inhibits Tumorigenesis in Cisplatin-Resistant Non-Small Cell Lung Cancer via TRPV2.

Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy to combat the growth of cisplatin-resistant (CR) NSCLC cells. We have shown that treatment with the plant-derived, non-psychotropic small molecular weight molecule, cannabidiol (CBD), significantly induced apoptosis of CR NSCLC cells. In addition, CBD treatment significantly reduced tumor progression and metastasis in a mouse xenograft model and suppressed cancer stem cell properties. Further mechanistic studies demonstrated the ability of CBD to inhibit the growth of CR cell lines by reducing NRF-2 and enhancing the generation of reactive oxygen species (ROS). Moreover, we show that CBD acts through Transient Receptor Potential Vanilloid-2 (TRPV2) to induce apoptosis, where TRPV2 is expressed on human lung adenocarcinoma tumors. High expression of TRPV2 correlates with better overall survival of lung cancer patients. Our findings identify CBD as a novel therapeutic agent targeting TRPV2 to inhibit the growth and metastasis of this aggressive cisplatin-resistant phenotype in NSCLC.

Lipopolysaccharide from the commensal microbiota of the breast enhances cancer growth: role of S100A7 and TLR4.

The role of commensal bacterial microbiota in the pathogenesis of human malignancies has been a research field of incomparable progress in recent years. Although breast tissue is commonly assumed to be sterile, recent studies suggest that human breast tissue may contain a bacterial microbiota. In this study, we used an immune-competent orthotopic breast cancer mouse model to explore the existence of a unique and independent bacterial microbiota in breast tumors. We observed some similarities in breast cancer microbiota with skin; however, breast tumor microbiota was mainly enriched with Gram-negative bacteria, serving as a primary source of lipopolysaccharide (LPS). In addition, dextran sulfate sodium (DSS) treatment in late-stage tumor lesions increased LPS levels in the breast tissue environment. We also discovered an increased expression of S100A7 and low level of TLR4 in late-stage tumors with or without DSS as compared to early-stage tumor lesions. The treatment of breast cancer cells with LPS increased the expression of S100A7 in breast cancer cells in vitro. Furthermore, S100A7 overexpression downregulated TLR4 and upregulated RAGE expression in breast cancer cells. Analysis of human breast cancer samples also highlighted the inverse correlation between S100A7 and TLR4 expression. Overall, these findings suggest that the commensal microbiota of breast tissue may enhance breast tumor burden through a novel LPS/S100A7/TLR4/RAGE signaling axis.

Fibroblast-derived CXCL12 increases vascular permeability in a 3-D microfluidic model independent of extracellular matrix contractility.

Cancer-associated fibroblasts (CAFs) play an active role in remodeling the local tumor stroma to support tumor initiation, growth, invasion, metastasis, and therapeutic resistance. The CAF-secreted chemokine, CXCL12, has been directly implicated in the tumorigenic progression of carcinomas, including breast cancer. Using a 3-D in vitro microfluidic-based microtissue model, we demonstrate that stromal CXCL12 secreted by CAFs has a potent effect on increasing the vascular permeability of local blood microvessel analogues through paracrine signaling. Moreover, genetic deletion of fibroblast-specific CXCL12 significantly reduced vessel permeability compared to CXCL12 secreting CAFs within the recapitulated tumor microenvironment (TME). We suspected that fibroblast-mediated extracellular matrix (ECM) remodeling and contraction indirectly accounted for this change in vessel permeability. To this end, we investigated the autocrine effects of CXCL12 on fibroblast contractility and determined that antagonistic blocking of CXCL12 did not have a substantial effect on ECM contraction. Our findings indicate that fibroblast-secreted CXCL12 has a significant role in promoting a leakier endothelium hospitable to angiogenesis and tumor cell intravasation; however, autocrine CXCL12 is not the primary upstream trigger of CAF contractility.

cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment.

BACKGROUND: Molecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear. METHODS: Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells. RESULTS: In this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients. CONCLUSIONS: Our study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer.

Racially Disparate Expression of mTOR/ERK-1/2 Allied Proteins in Cancer.

Recent studies revealed that ethnic differences in mechanistic target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK-1/2) signaling pathways might be associated with the development and progression of different human malignancies. The African American (AA) population has an increased rate of cancer incidence and mortality compared to the Caucasian American (CA) population. Although the socioeconomic differences across different ethnic groups contribute to the disparity in developing different cancers, recent scientific evidence indicates the association of molecular and genetic variations in racial disparities of different human malignancies. The mTOR and ERK-1/2 signaling pathways are one of the well-known oncogenic signaling mechanisms that regulate diverse molecular and phenotypic aspects of normal as well as cancer cells in response to different external or internal stimuli. To date, very few studies have been carried out to explore the significance of racial disparity with abnormal mTOR and ERK-1/2 kinase signaling pathways, which may contribute to the development of aggressive human cancers. In this review, we discuss the differential regulation of mTOR and ERK-1/2 kinase signaling pathways across different ethnic groups, especially between AA and CA populations. Notably, we observed that key signaling proteins associated with mTOR and ERK-1/2 pathway including transforming growth factor-beta (TGF-ß), Akt, and VEGFR showed racially disparate expression in cancer patients. Overall, this review article encompasses the significance of racially disparate signaling molecules related to mTOR/ERK1/2 and their potential in developing tailor-made anti-cancer therapies.

Slit2 Inhibits Breast Cancer Metastasis by Activating M1-Like Phagocytic and Antifibrotic Macrophages.

Tumor-associated macrophages (TAM) are heterogeneous in nature and comprise antitumor M1-like (M1-TAM) or pro-tumor M2-like (M2-TAM) TAMs. M2-TAMs are a major component of stroma in breast tumors and enhance metastasis by reducing their phagocytic ability and increasing tumor fibrosis. However, the molecular mechanisms that regulate phenotypic plasticity of TAMs are not well known. Here we report a novel tumor suppressor Slit2 in breast cancer by regulating TAMs in the tumor microenvironment. Slit2 reduced the in vivo growth and metastasis of spontaneous and syngeneic mammary tumor and xenograft breast tumor models. Slit2 increased recruitment of M1-TAMs to the tumor and enhanced the ability of M1-TAMs to phagocytose tumor cells in vitro and in vivo. This Slit2-mediated increase in M1-TAM phagocytosis occurred via suppression of IL6. Slit2 was also shown to diminish fibrosis in breast cancer mouse models by increasing the expression of matrix metalloproteinase 13 in M1-TAMs. Analysis of patient samples showed high Slit2 expression strongly associated with better patient survival and inversely correlated with the abundance of CD163+ TAMs. Overall, these studies define the role of Slit2 in inhibiting metastasis by activating M1-TAMs and depleting tumor fibrosis. Furthermore, these findings suggest that Slit2 can be a promising immunotherapeutic agent to redirect TAMs to serve as tumor killers for aggressive and metastatic breast cancers. In addition, Slit2 expression along with CD163+ TAMs could be used as an improved prognostic biomarker in patients with breast cancer. SIGNIFICANCE: This study provides evidence that the antitumor effect of Slit2 in breast cancer occurs by activating the phagocytic activity of M1-like tumor-associated macrophages against tumor cells and diminishing fibrosis.

An AI-based approach in determining the effect of meteorological factors on incidence of malaria

This study presents the classification of malaria-prone zones based on (a) meteorological factors, (b) demographics and (c) patient information. Observations are performed on extended features in dataset over the spiking and non-spiking classifiers including Quadratic Integrate and Fire neuron (QIFN) model as a benchmark. As per research studies, parasite transmission is highly dependent on the (i) stagnant water, (ii) population of area and the (iii) greenery of the locality. Considering these factors, three more attributes were added to the existing novel dataset and comparison on the results is presented. For four feature dataset, QIFN exhibited an accuracy of 97.08% in K10 protocol, and with extended dataset; QIFN yields an accuracy of 99.58% in K10 protocol. The benchmarking results showed reliability and stability. There is 12.47% improvement against multilayer perceptron (MLP) and 5.39% against integrate-and-fire neuron (IFN) model. The QIFN model performed the best over the conventional classifiers for deciphering the risk of acquiring malaria in different geographical regions worldwide.

A new backpropagation neural network classification model for prediction of incidence of malaria.

Malaria is an infectious disease caused by parasitic protozoans of the Plasmodium family. These parasites are transmitted by mosquitos which are common in certain parts of the world. Based on their specific climates, these regions have been classified  as low and high risk regions using a backpropagation neural network (BPNN). However, this approach yielded low performance and stability necessitating development of a more robust model. We hypothesized that by spiking neuron models in simulating the characteristics of a neuron, which when embedded with a BPNN, could improve the performance for the assessment of malaria prone regions. To this end, we created an inter-spike interval (ISI)-based BPNN (ISI-BPNN) architecture that uses a single-pass spiking learning strategy and has a parallel structure that is useful for non-linear regression tasks. Existing malaria dataset comprised of 1296 records, that met these attributes, were used. ISI-BPNN showed superior performance, and a high accuracy. The benchmarking results showed reliability and stability and an improvement of 11.9% against a multilayer perceptron and 9.19% against integrate-and-fire neuron models. The ISI-BPNN model is well suited for deciphering the risk of acquiring malaria as well as other diseases in prone regions of the world.

Silymarin, a polyphenolic flavonoid impede Plasmodium falciparum growth through interaction with heme.

A polyphenolic flavonoid, Silymarin isolated from Silybum marianum is widely known for its hepatoprotective action. In the present study anti-plasmodial activity of Silymarin has been demonstrated for the first time having IC50 of 14 ± 0.33 µM against the NF-54 strain of P. falciparum with high selectivity index (>100). The parasitostatic action is exerted through inhibition of ß-hematin/hemozoin formation which is due to the interaction (Kd = 3.63 ± 0.9µM) of silymarin with free heme in a Stoichiometry of 1:1 Silymarin: heme complex resulting into heme-induced membrane damage in the parasite. Silymarin could hinder the glutathione and hydrogen peroxide-induced heme detoxification. Silymarin also induces apoptosis in the parasite through the elevation of caspase-3 level in a dose-dependent manner. Results from the docking studies suggest that Silymarin interacts with heme.

Cancer data classification using binary bat optimization and extreme learning machine with a novel fitness function.

Cancer classification is one of the crucial tasks in medical field. The gene expression of cells helps in identifying the cancer. The high dimensionality of gene expression data hinders the classification performance of any machine learning models. Therefore, we propose, in this paper a methodology to classify cancer using gene expression data. We employ a bio-inspired algorithm called binary bat algorithm for feature selection and extreme learning machine for classification purpose. We also propose a novel fitness function for optimizing the feature selection process by binary bat algorithm. Our proposed methodology has been compared with original fitness function that has been found in the literature. The experiments conducted show that the former outperforms the latter. Graphical Abstract Classification using Binary Bat Optimization and Extreme Learning Machine.

Isoniazid induces apoptosis: Role of oxidative stress and inhibition of nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2).

AIMS: Long-term treatment of Isoniazid (INH) in tuberculosis (TB) patients can lead to anti-tuberculosis drug-induced hepatotoxicity. To understand the mechanism of hepatotoxicity, an attempt has been made to elucidate the role of Nrf2, a transcription factor induced by oxidative stress, in INH induced apoptosis liver cancer cell lines. MATERIALS AND METHODS: Cytotoxicity was evaluated by MTT assay. Apoptosis and reactive oxygen species (ROS) generation was performed by flow cytometry. mRNA and protein expression of various genes involves in INH induced toxicity was evaluated via Real-time PCR and western blot analysis respectively. Differential protein expression was performed by two-dimensional gel electrophoresis followed by identification using MALDI TOF/TOF. KEY FINDINGS: INH induced ROS and apoptosis in HepG2 as well as THLE-2 cells. Nuclear damage was also observed by INH treatment in HepG2 cells. Expression of apoptotic (Cytochrome C and Caspase 9) and antioxidative (Keap1 and Nrf2) genes were observed to increase. INH induced PKCδ phosphorylation and released Nrf2 from its inhibitor Keap1 in the cytoplasm of HepG2 cells. However, over-expression of Nrf2 did not affect nuclear Nrf2 protein level as well as its downstream target NQO1. Nrf2 importer, Karyopherin ß1 level was observed to decrease in HepG2 as well as THLE-2 cells following INH treatment. SIGNIFICANCE: These findings suggest that INH prevented Nrf2 translocation into the nucleus by inhibiting its importer Karyopherin ß1. Therefore Nrf2 might not able to bind ARE sequences from inducing antioxidative response for protecting the cells undergoing apoptosis.

Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis.

Isoniazid is used either alone or in combination with other drugs for the treatment of tuberculosis. It is also used for the prevention of tuberculosis. Chronic treatment of Isoniazid may cause severe liver damage leading to acute liver failure. The mechanism through which Isoniazid causes liver damage is investigated. Isoniazid treatment generates reactive oxygen species and induces apoptosis in Hep3B cells. It induces antioxidative and apoptotic genes leading to increase in mRNA expression and protein levels in Hep3B cells. Whole genome expression analysis of Hep3B cells treated with Isoniazid has resulted in differential expression of various genes playing prime role in regulation of apoptotic, antioxidative, DNA damage, cell signaling, cell proliferation and differentiation pathways. Isoniazid increased cytosolic Nrf2 protein level while decreased nuclear Nrf2 protein level. It also decreased ERK1 phosphorylation and treatment of Hep3B cells with ERK inhibitor followed by Isoniazid resulting in increased apoptosis in these cells. Two dimensional gel electrophoresis results have also shown differential expression of various protein species including heat shock proteins, proteins playing important role in oxidative stress, DNA damage, apoptosis, cell proliferation and differentiation. Results suggest that Isoniazid induces apoptosis through oxidative stress and also prevents Nrf2 translocation into the nucleus by reducing ERK1 phosphorylation thus preventing cytoprotective effect.

Rosiglitazone induces cardiotoxicity by accelerated apoptosis.

Present investigation explores the cardiotoxicity of rosiglitazone (ROSI) using rat heart cardiomyocytes and db/db mice. In H9c2 cells, ROSI at 50 and 60 µM induced an increase in the percentage of apoptotic cells and superoxide generation, along with an increase in the expression of various subunits of NADPH oxidase and nitric oxide synthases, confirmed that ROSI-induced apoptosis in H9c2 cells is by ROS generation. The increase in the expression of the antioxidants like superoxide dismutase (SOD), catalase, glutathione reductase (GR), glutathione-S-transferase (GST), and glutathione peroxidase (GPx) further confirmed this notion. Heme oxygenase-1, having an important role in cell protection against oxidative stress, was found to be increased along with induction of nuclear translocation of NF-E2-related factor and increased protein kinase C δ expression. Moreover, in db/db mice, oral administration of ROSI (10 mg/kg) for 10 days induced an increase in serum creatinine kinase-MB, tissue antioxidants like SOD, catalase, GR, GST, GPx expression, cardiac troponin T, and inducible nitric oxide synthase protein expression strongly support the in vitro findings. Furthermore, global gene expression studies also showed the perturbation of oxidative phosphorylation, fat cell differentiation, and electron transport chain following ROSI treatment in vivo. These results suggested that ROSI-induced cardiac damage is due to accelerated apoptosis both in vitro and in vivo.