ABSTRACT
For decades, guinea worm disease, caused by the parasitic worm Dracunculus medinensis, has been a major public health concern, impacting vulnerable populations in Africa and Asia. This review gives an in-depth examination of the various therapeutic approaches used to combat guinea worm disease. This study seeks to provide a current and evidence-based summary of available treatment techniques by conducting an exhaustive examination of peer-reviewed literature, medical databases, and official health organisation publications. The current review intends to contribute to the knowledge base and influence plans for guinea worm disease control and eradication by critically evaluating the success and obstacles associated with various treatment approaches through standard heterocyclic medications, herbal sources, phytochemicals, and nanomedicines. The importance of integrating community engagement and collaboration among national and international stakeholders is emphasised to foster sustainable solutions and ensure a collective effort towards a guinea worm-free world.
ABSTRACT
BACKGROUND: This systematic review and meta-analysis aimed to compare the efficacy and safety of cangrelor as compared to ticagrelor in patients with ST-elevated myocardial infarction (STEMI) who underwent percutaneous intervention. METHODS: PubMed, Embase, Scopus, Web of Science, Cochrane CENTRAL, and ClinicalTrials.gov databases were searched for relevant head-on-comparison or swapping studies. The primary outcome was the rate of high platelet reactivity (HPR) at specific time intervals after stopping cangrelor infusion during the first 24 h. Secondary outcomes were the risks of thrombosis, all-cause mortality and bleeding. Pooled odds ratios (ORs) were calculated using random-effects models. RESULTS: A total of 1018 studies were screened and eight were included in the analysis. There were four head-on-comparison studies and four swapping studies. There was no significant difference in the proportion of patients achieving a high platelet reactivity in swapping studies [OR, 0.71 (95% CI 0.04, 13.87), p = 0.82, i2 = 88%]. In head-on-comparison studies, PRU from Fig. 2B shows there was no significant reduction in high platelet reactivity [mean difference - 77.83 (95% CI - 238.84, 83.18), p < 0.001, i2 = 100%]. PRU results from (Fig. 2C) show a mean difference of 7.38 (95% CI - 29.74, 44.51), p < 0.001, i2 = 97%. There was no significant difference in the risks of thrombosis [OR, 0.91 (95% CI 0.20, 4.13), p = 0.81, i2 = 0%], all-cause mortality [OR, 3.52 (95% CI 0.44, 27.91), p = 0.24, i2 = 26%] and bleeding [OR, 0.89 (95% CI 0.37, 2.17), p = 0.93, i2 = 0%] between the two groups as revealed in the head-on-comparison studies. CONCLUSION: The efficacy and safety profiles of cangrelor and ticagrelor were similar in patients with STEMI.
ABSTRACT
A combination of chemotherapy with immunotherapy has been proposed to have better clinical outcomes in Pancreatic Ductal Adenocarcinoma (PDAC). On the other hand, chemotherapeutics is known to have certain unwanted effects on the tumor microenvironment that may mask the expected beneficial effects of immunotherapy. Here, we have investigated the effect of gemcitabine (GEM), on two immune checkpoint proteins (PD-L1 and PD-L2) expression in cancer associated fibroblasts (CAFs) and pancreatic cancer cells (PCCs). Findings of in vitro studies conducted by using in-culture activated mouse pancreatic stellate cells (mPSCs) and human PDAC patients derived CAFs demonstrated that GEM significantly induces PD-L1 and PD-L2 expression in these cells. Moreover, GEM induced phosphorylation of STAT1 and production of multiple known PD-L1-inducing secretory proteins including IFN-γ in CAFs. Upregulation of PD-L1 in PSCs/CAFs upon GEM treatment caused T cell inactivation and apoptosis in vitro. Importantly, Statins suppressed GEM-induced PD-L1 expression both in CAFs and PCCs while abrogating the inactivation of T-cells caused by GEM-treated PSCs/CAFs. Finally, in an immunocompetent syngeneic orthotopic mouse pancreatic tumor model, simvastatin and GEM combination therapy significantly reduced intra-tumor PD-L1 expression and noticeably reduced the overall tumor burden and metastasis incidence. Together, the findings of this study have provided experimental evidence that illustrates potential unwanted side effects of GEM that could hamper the effectiveness of this drug as mono and/or combination therapy. At the same time the findings also suggest use of statins along with GEM will help in overcoming these shortcomings and warrant further clinical investigation.
Subject(s)
Cancer-Associated Fibroblasts , Carcinoma, Pancreatic Ductal , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Pancreatic Neoplasms , Animals , Humans , Mice , B7-H1 Antigen/metabolism , Cancer-Associated Fibroblasts/pathology , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Gemcitabine , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Pancreatic Neoplasms/pathology , Treatment Outcome , Tumor MicroenvironmentABSTRACT
Amalgamation of target-based approach along with chemo and/or radiotherapy could be an effective strategy to combat pancreatic cancer (PC). ATAD2 (ATPase family AAA domain containing 2) is a potential oncoprotein and a poor prognostic factor in PC. ATAD2 inhibition sensitizes pancreatic cancer cells (PCCs) to gemcitabine (GEM). ATAD2 silencing also enhances radio-sensitivity in lung cancer cells. We therefore hypothesise that ATAD2 suppression along with application of GEM and radiation could show additive/synergistic response in reducing PC progression. At first, immunofluorescence and western blot analysis are carried out to investigate ATAD2 expression upon irradiation in PCCs (BxPC3, and PANC1). Colony forming assay is performed to analyse the radio-sensitization effect of ATAD2 suppressed PCCs in absence and presence of GEM. To evaluate the consequences of irradiation, expression of markers for DNA damage and repair as well as apoptosis and autophagy are also assessed. Results indicate that ATAD2 is elevated in irradiated PCCs. Silencing ATAD2 sensitizes PCCs to radiation. Survival fraction analysis of PCCs shows that combination treatment of GEM and radiation (with minimal doses) is more effective when ATAD2 is suppressed. Further, when GEM-radiation combination is applied to ATAD2 silenced PCCs, expression of DNA damage marker like γH2AX is induced, whereas DNA damage repair proteins (pChk1, and pChk2) are downregulated. Moreover, ATAD2 suppressed PCCs are more susceptible to apoptosis and autophagy in presence of radiation and GEM. Collectively, these findings support our hypothesis and demonstrate that targeting ATAD2 enhances efficacy of GEM-radiation treatment in PCCs.
Subject(s)
Deoxycytidine , Pancreatic Neoplasms , Humans , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Pancreatic Neoplasms/metabolism , Cell Line, Tumor , ATPases Associated with Diverse Cellular Activities/genetics , ATPases Associated with Diverse Cellular Activities/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gemcitabine , Pancreatic NeoplasmsABSTRACT
The exchange of CO2 between the air-water interfaces of estuaries is crucial from the perspective of the global carbon cycle and climate change feedback. In this regard, we evaluated the air-water CO2 exchanges in two major estuaries-the Mahanadi estuary (ME) and the Dhamra estuary (DE) in the northern part of the Bay of Bengal, India. Biogeochemical properties of these estuarine waters were quantified in three distinct seasons, namely, pre-monsoon (March to May), monsoon (June to October), and post-monsoon (November to February). The significant properties of water, such as the water temperature, pH, salinity, nutrients, dissolved oxygen, chlorophyll-a (chl a), and photosynthetic pigment fluorescence of phytoplankton, were estimated and correlated with CO2 fluxes. We found that the ME acted as a source of CO2 fluxes in the monsoon and post-monsoon, while DE acted as a sink during the monsoon. The stepwise regression model showed that the fluxes were primarily driven by water temperature, pH, and salinity, and they correlated well with the phytoplankton characteristics. The chl a content, fluorescence yield, and phycobilisomes-to-photosystem II fluorescence ratios were major drivers of the fluxes. Therefore, for predicting air-water CO2 exchanges precisely in a large area over a seasonal and annual scale in the estuaries of the Bay of Bengal, India, critical key parameters such as water temperature, pH, salinity, chl a, and fluorescence yield of phytoplankton should be taken into consideration. However, the responses of phytoplankton, both in terms of production and CO2 capture, are critical research areas for a better understanding of air-water CO2 exchanges in coastal ecology under climate change scenarios.
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Zebrafish are extensively used in several kinds of research because they are one of the easily maintained vertebrate models and exhibit several features of a unique and convenient model system. As highly proliferative cells are more susceptible to radiation-induced DNA damage, zebrafish embryos are a front-line in vivo model in radiation research. In addition, this model projects the effect of radiation and different drugs within a short time, along with major biological events and associated responses. Several cancer studies have used zebrafish, and this protocol is based on the use of radiation modifiers in the context of radiotherapy and cancer. This method can be readily used to validate the effects of different drugs on irradiated and control (non-irradiated) embryos, thus identifying drugs as radio sensitizing or protective drugs. Although this methodology is used in most drug screening experiments, the details of the experiment and the toxicity assessment with the background of X-ray radiation exposure are limited or only briefly addressed, making it difficult to perform. This protocol addresses this issue and discusses the procedure and toxicity evaluation with a detailed illustration. The procedure describes a simple approach for using zebrafish embryos for radiation studies and radiation-based drug screening with much reliability and reproducibility.
Subject(s)
Zebrafish , Animals , Drug Evaluation, Preclinical , Larva/radiation effects , Reproducibility of Results , X-Rays , Zebrafish/geneticsABSTRACT
The presence of activated pancreatic stellate cells (PSCs) in the pancreatic ductal adenocarcinoma (PDAC) microenvironment plays a significant role in cancer progression. Macrophage migration inhibitory factor (MIF) is overexpressed in PDAC tissues and expressed by both cancer and stromal cells. The pathophysiological role of MIF in PDAC-associated fibroblasts or PSCs is yet to be elucidated. Here we report that the PSCs of mouse or cancer-associated fibroblast cells (CAFs) of human expresses MIF and its receptors, whose expression gets upregulated upon LPS or TNF-α stimulation. In vitro functional experiments showed that MIF significantly conferred a survival advantage to CAFs/PSCs upon growth factor deprivation. Genetic or pharmacological inhibition of MIF also corroborated these findings. Further, co-injection of mouse pancreatic cancer cells with PSCs isolated from Mif-/- or Mif+/+ mice confirmed the pro-survival effect of MIF in PSCs and also demonstrated the pro-tumorigenic role of MIF expressed by CAFs in vivo. Differential gene expression analysis and in vitro mechanistic studies indicated that MIF expressed by activated CAFs/PSCs confers a survival advantage to these cells by suppression of interferon pathway induced p53 dependent apoptosis.
Subject(s)
Apoptosis , Cancer-Associated Fibroblasts , Carcinoma, Pancreatic Ductal , Macrophage Migration-Inhibitory Factors , Pancreatic Neoplasms , Animals , Apoptosis/genetics , Apoptosis/physiology , Cancer-Associated Fibroblasts/metabolism , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor/metabolism , Cell Movement , Cell Proliferation , Humans , Interferons/metabolism , Intramolecular Oxidoreductases/genetics , Intramolecular Oxidoreductases/metabolism , Macrophage Migration-Inhibitory Factors/genetics , Macrophage Migration-Inhibitory Factors/metabolism , Mice , Pancreatic Neoplasms/pathology , Tumor Microenvironment , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Pancreatic NeoplasmsABSTRACT
OBJECTIVES: Covishield and Covaxin vaccines have been introduced after rapid approval in India, the nation that has the second most COVID-19 cases globally. These vaccines have been administered in a 2-dose schedule since January 16, 2021. This study deals with the clinical profile of individuals who developed COVID-19 infection post COVID-19 vaccination. This is the first study of its kind in India. STUDY DESIGN: Descriptive cross-sectional study. METHODS: The study population was composed of individuals who were COVID-19 positive more than 4 weeks post vaccination and were compared with individuals who were COVID-19 positive within the first 4 weeks of vaccination. Data were collected in a digital questionnaire format and analyzed with SPSS version 23 software. Clinical features were profiled in detail. Chi-square analysis was done to find out the association of various demographic features with the severity of the disease. RESULTS: In the study population, fever was the most common symptom (75.1%), followed by anosmia (72.1%) and shortness of breath (16.3%). There was a lower incidence of fever, cough, dyspnea, and requirement of hospitalization in the study population compared with the control group and previous epidemiological data. The time required for complete recovery and disease severity was favorable in our study population. There was a significant correlation in the rate of hospitalization among the study group and the comparative group (P = .0001) and between the number of doses of COVID-19 vaccine and the lowest oxygen saturation recorded (P = .001). CONCLUSIONS: The findings of this study should boost the ongoing initiative of maximizing the vaccinated population countrywide and emphasize the need for 2 doses of vaccination.
Subject(s)
COVID-19 Vaccines , COVID-19 , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , ChAdOx1 nCoV-19 , Cross-Sectional Studies , Humans , Vaccination , VaccinesABSTRACT
In patients with pancreatic cancer (PC), the peritoneal cavity is the second-most common site of metastasis after the liver. Peritoneal macrophages (PMs) have been demonstrated to play a significant role in the peritoneal metastases of different cancers. Gemcitabine (GEM) is known to affect PC-associated immune cells, including macrophages. However, its effect on PMs and its possible clinical implication is yet to be investigated. In this study, mouse-derived PMs were treated with GEM ex vivo to analyze the polarization status. Production of GEM-induced reactive oxygen species (ROS) and reactive nitrogen species was evaluated using DCFH-DA, DAF-FM, and Griess assay. Antitumor effects of PMs on UN-KC-6141and UN-KPC-961 murine PC cells were evaluated in presence and absence of GEM in vitro. Similarly, effect of GEM on human THP-1 macrophage polarization and its tumoricidal effect was studied in vitro. Furthermore, the effect of GEM-treated PMs on peritoneal metastasis of UN-KC-6141 cells was evaluated in a syngeneic mouse model of PC. GEM upregulated M1 phenotype-associated molecular markers (Tnf-α and Inos) in vitro in PMs obtained from naïve mouse. Moreover, IL-4-induced M2-like PMs reverted to M1-like after GEM treatment. Co-culture of UN-KC-6141 and UN-KPC-961 cancer cells with PMs in the presence of GEM increased apoptosis of these cells, whereas cell death was markedly reduced after N-acetyl-L-cysteine treatment. Corroborating these findings co-culture of GEM-treated human THP-1 macrophages also induced cell death in MIAPaCa-2 cancer cells. GEM-treated PMs injected intraperitoneally along with UN-KC-6141 cells into mice extended survival period, but did not stop disease progression and mortality. Together, GEM induced M1-like polarization of PMs from naive and/or M2-polarized PMs in a ROS-dependent manner. GEM-induced M1-like PMs prompted cytotoxicity in PC cells and delayed disease progression in vivo.
Subject(s)
Macrophages, Peritoneal , Macrophages , Animals , Deoxycytidine/analogs & derivatives , Disease Progression , Humans , Macrophages, Peritoneal/metabolism , Mice , Reactive Oxygen Species/metabolism , GemcitabineABSTRACT
AIMS: Pancreatic cancer is a fatal disease across the world with 5 years survival rate less than 10%. ATAD2, a valid cancer drug-target, is overexpressed in pancreatic malignancy with high oncogenic potential. However, the mechanism of the upregulated expression of ATAD2 in pancreatic cancer is unknown. Since microRNAs (miRNAs) could potentially control target mRNA expressions, and are involved in cancer as tumor-suppressors, oncomiR or both, we examine the possibility of miRNA-mediated regulation of ATAD2 in pancreatic cancer cells (PCCs). MAIN METHODS: Our in-silico approach first identifies hsa-miR-217 as a candidate regulator for ATAD2 expression. For further validation, luciferase reporter assay is performed. We overexpress hsa-miRNA-217 and assess cellular viability, migration, apoptosis and cell cycle progression in three different PCCs (BxPC3, PANC1, and MiaPaCa2). KEY FINDINGS: We find hsa-miRNA-217 has potential binding site at the 3'UTR of ATAD2. Luciferase assay confirms that ATAD2 is a direct target of hsa-miR-217. Overexpression of hsa-miR-217 drastically downregulates ATAD2 expression in PCCs, thus, corroborating binding studies. The elevated expression of hsa-miRNA-217 diminishes cell proliferation and migration as well as induces apoptosis and cell cycle arrest in PCCs. Finally, siRNA mediated ATAD2 knockdown or overexpression of hsa-miRNA-217 in PCCs showed inactivation of the AKT signaling pathway. Therefore, hsa-miR-217 abrogates pancreatic cancer progression through inactivation of the AKT signaling pathway and this might be partly due to miR-217 mediated suppression of ATAD2 expression. SIGNIFICANCE: The application of hsa-miR-217 mimic could be a promising therapeutic strategy for the treatment of pancreatic cancer patients in near future.
Subject(s)
MicroRNAs , Pancreatic Neoplasms , ATPases Associated with Diverse Cellular Activities/genetics , ATPases Associated with Diverse Cellular Activities/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Neoplastic , Humans , Luciferases/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins c-akt/metabolism , Pancreatic NeoplasmsABSTRACT
Pancreatic cancer (PC) is highly resistant to chemo and radiotherapy. Radiation-induced fibrosis (RIF) is a major cause of clinical concern for various malignancies, including PC. In this study, we aimed to evaluate the radiosensitizing and anti-RIF potential of fluvastatin in PC. Short-term viability and clonogenic survival assays were used to evaluate the radiosensitizing potential of fluvastatin in multiple human and murine PC cell lines. The expression of different proteins was analyzed to understand the mechanisms of fluvastatin-mediated radiosensitization of PC cells and its anti-RIF effects in both mouse and human pancreatic stellate cells (PSCs). Finally, these effects of fluvastatin and/or radiation were assessed in an immune-competent syngeneic murine model of PC. Fluvastatin radiosensitized multiple PC cell lines, as well as radioresistant cell lines in vitro, by inhibiting radiation-induced DNA damage repair response. Nonmalignant cells, such as PSCs and NIH3T3 cells, were less sensitive to fluvastatin-mediated radiosensitization than PC cells. Interestingly, fluvastatin suppressed radiation and/or TGF-ß-induced activation of PSCs, as well as the fibrogenic properties of these cells in vitro. Fluvastatin considerably augmented the antitumor effect of external radiation therapy and also suppressed intra-tumor RIF in vivo. These findings suggested that along with radiation, fluvastatin co-treatment may be a potential therapeutic approach against PC.
Subject(s)
Fluvastatin/pharmacology , Pancreatic Neoplasms/pathology , Radiation Tolerance/drug effects , Transforming Growth Factor beta/pharmacology , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , Autophagy/drug effects , Autophagy/radiation effects , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/radiation effects , Cells, Cultured , Embryo, Nonmammalian/drug effects , Embryo, Nonmammalian/embryology , Embryo, Nonmammalian/radiation effects , Fibrosis/prevention & control , Humans , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/radiotherapy , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Zebrafish/embryologyABSTRACT
BACKGROUND: The role of microbiota in the pathophysiology of benign prostate hyperplasia (BPH), especially in creating an inflammatory milieu may not be avoided. The major objectives of this study were to investigate the microbial composition of BPH tissues, its association with inflammation and check the effect of clinically isolated bacteria on prostate epithelial cells. METHODS: The study includes 36 patients with a pathological diagnosis of BPH. Following strict aseptic measures, tissues were collected after transurethral resection of prostate, multiple pieces of the resected tissues were subjected to histopathological analysis, bacterial culture and genomic DNA extraction. Microbial composition was analyzed by culture and/or next-generation sequencing methods. Annotation of operational taxonomy unit has been done with an in-house algorithm. The extent of inflammation was scored through histological evaluation of tissue sections. The effect of clinical isolates on nuclear factor-κB (NF-κB) activity and induction of DNA-damage in the prostate epithelial cells were evaluated. RESULTS: Histopathological analysis of the BPH tissues showed the presence of inflammation in almost all the tissues with a varied level at different regions of the same tissue section and the level of overall inflammation was different from patients to patients. Microbial culture of tissue samples showed the presence of live bacteria in 55.5% (20 out of 36) of the patient tissues. Majority of the isolates were coagulase-positive Staphylococcus, E. coli and Micrococcus spp. Further, V3 16S rRNA sequencing of the DNA isolated from BPH tissues showed the presence of multiple bacteria and the most common phylum in the BPH tissues were found to be Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes. The E. coli, isolated from one of the tissue was able to activate NF-κB and induce DNA damage in prostate epithelial cells. Phospho-histone γH2A.X staining confirmed the presence of cells with damaged DNA lesion in BPH tissues and also correlated with the severity of inflammation. CONCLUSION: Our study has shown that the BPH tissues do have a divergent microbial composition including the commonly found E. coli (phylum Proteobacteria), and these bacteria might contribute to the BPH-associated inflammation and/or tissue damage. The BPH-associated E. coli induced NF-κB signaling and DNA damage in prostate epithelial cells in vitro.
Subject(s)
DNA Damage , Epithelial Cells/microbiology , Escherichia coli/isolation & purification , Inflammation/microbiology , Prostate/microbiology , Prostatic Hyperplasia/microbiology , Epithelial Cells/pathology , Humans , Inflammation/pathology , Male , Middle Aged , Prostate/pathology , Prostate/surgery , Prostatic Hyperplasia/pathology , Prostatic Hyperplasia/surgery , Transurethral Resection of ProstateABSTRACT
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that increasingly is being studied in cancers and inflammatory diseases. Though murine models have been instrumental in understanding the functional role of MIF in different pathological conditions, the information obtained from these models is biased towards a specific species. In experimental science, results obtained from multiple clinically relevant animal models always provide convincing data that might recapitulate in humans. Syrian golden hamster (Mesocricetus auratus), is a clinically relevant animal model for multiple human diseases. Hence, the major objectives of this study were to characterize the structure and function of Mesocricetus auratus MIF (MaMIF) and finally evaluate its effect on pancreatic tumor growth in vivo. Initially, the recombinant MaMIF was cloned, expressed and purified in a bacterial expression system. The MaMIF primary sequence, biochemical properties, and crystal structure analysis showed greater similarity with human MIF. The crystal structure of MaMIF illustrates that it forms a homotrimer as known in human and mouse. However, MaMIF exhibits some minor structural variations when compared to human and mouse MIF. The in vitro functional studies show that MaMIF has tautomerase activity and enhances activation and migration of hamster peripheral blood mononuclear cells (PBMCs). Interestingly, injection of MaMIF into HapT1 pancreatic tumor-bearing hamsters significantly enhanced the tumor growth and tumor-associated angiogenesis. Together, the current study shows a structural and functional similarity between the hamster and human MIF. Moreover, it has demonstrated that a high level of circulating MIF originating from non-tumor cells might also promote pancreatic tumor growth in vivo.
Subject(s)
Macrophage Migration-Inhibitory Factors/physiology , Pancreatic Neoplasms/physiopathology , Amino Acid Sequence , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation/physiology , Crystallography, X-Ray , Gene Knockdown Techniques , Humans , Leukocytes, Mononuclear/cytology , Macrophage Migration-Inhibitory Factors/chemistry , Macrophage Migration-Inhibitory Factors/genetics , Mesocricetus , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Phylogeny , Protein Conformation , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Sequence Homology, Amino Acid , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Metastatic prostate cancer, with no effective treatment, is among the leading causes of cancer-associated deaths in men. Overexpression of p38αMAPK has been observed in neuroendocrine prostate cancer patients and in both DU145 and PC-3 cell lines and represents a good drug target. Sulfonamide derivatives have shown biological activities against many human diseases, including cancer. CID-6033590, a sulfonylhydrazide compound, screened from PubChem database by molecular docking with p38αMAPK, was evaluated for anti-cancerous activities. CID-6033590 induced toxicity in both DU145 and PC-3 cells in a concentration and time-dependent manner with an IC50 value of 60⯵M and 66⯵M, respectively. Sub-cytotoxic concentrations of the compound significantly induced S-phase cell cycle arrest, inhibited cyclinA/CDK2 complex and blocked cell proliferation. Further, CID-6033590 downregulated phosphorylation of p38MAPK (P-p38) as well as its downstream targets, Activating transcription factor 2 (ATF-2) and Heat shock protein 27 (Hsp27). The compound increased ROS and decreased mitochondrial membrane potential (Δψm), downregulated Bcl-2 and survivin and cleaved poly ADP ribose polymerase (PARP) and caspase-3, indicating the induction of apoptosis. The evaluaion of the compound on noncancerous, human prostatic epithelial cell line RWPE-1, and healthy murine tissues yielded no significant toxicity. Taken together, we suggest CID-6033590 as a potential candidate for prostate cancer therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Hydrazones/pharmacology , Prostatic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Catalase/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line , Glutathione/metabolism , Humans , Male , Mice, Inbred BALB C , Prostatic Neoplasms/metabolism , Reactive Oxygen Species/metabolism , S Phase/drug effects , Superoxide Dismutase/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Recovery of acetic acid (HAc) from the waste etching solution discharged from silicon wafer manufacturing process has been attempted by using solvent extraction process. For this purpose 2-ethylhexyl alcohol (EHA) was used as organic solvent. In the pre-treatment stage >99% silicon and hydrofluoric acid was removed from the solution by precipitation. The synthesized product, Na(2)SiF(6) having 98.2% purity was considered of commercial grade having good market value. The waste solution containing 279 g/L acetic acid, 513 g/L nitric acid, 0.9 g/L hydrofluoric acid and 0.030 g/L silicon was used for solvent extraction study. From the batch test results equilibrium conditions for HAc recovery were optimized and found to be 4 stages of extraction at an organic:aqueous (O:A) ratio of 3, 4 stages of scrubbing and 4 stages of stripping at an O:A ratio of 1. Deionized water (DW) was used as stripping agent to elute HAc from organic phase. In the whole batch process 96.3% acetic acid recovery was achieved. Continuous operations were successfully conducted for 100 h using a mixer-settler to examine the feasibility of the extraction system for its possible commercial application. Finally, a complete process flowsheet with material balance for the separation and recovery of HAc has been proposed.
Subject(s)
Acetic Acid/isolation & purification , Acids/chemistry , Semiconductors , Solvents/chemistry , X-Ray DiffractionABSTRACT
A process was developed to recover nitric acid from the waste stream of wafer industry using solvent extraction technique. Tributyl phosphate (TBP) was selected among several extractants because of its better selectivity towards HNO(3), overall superiority in operation, favorable physical properties and economics. The waste solution containing 260 g/L CH(3)COOH, 460 g/L HNO(3), 113 g/L HF and 19.6g/L Si was used as feed solution for process optimization. In the pre-treatment stage >99% silicon and hydrofluoric acid was precipitated out as Na(2)SiF(6). Equilibrium conditions for HNO(3) recovery were optimized from the batch test results as: four stages of extraction at an organic:aqueous (O:A) ratio of 3, four stages of scrubbing at O:A ratio of 5 and five stages of stripping at an O:A ratio of 1.5. The extraction of HNO(3) was suppressed by the presence of acetic acid (HAc) in the feed solution. To examine the feasibility of the extraction system a continuous operation was carried out for 200 h using a multistage mixer-settler. The concentration of pure HNO(3) recovered was 235 g/L with a purity of 99.8%.
Subject(s)
Industrial Waste , Nitric Acid/isolation & purification , Organophosphates , Solutions , SolventsABSTRACT
The present work deals with the As(V) removal from an aqueous medium by calcined refractory grade bauxite (CRB) as a function of solution pH, time, As(V) concentration and temperature. The residual As(V) was lowered from 2 mg/L to below 0.01 mg/L in the optimum pH range 4.0-7.0 using a 5 g/L CRB within 3 h contact time. The adsorption data fits well with Langmuir isotherm and yielded Langmuir monolayer capacity of 1.78 mg As(V)/g of CRB at pH 7.0. Presence of anions such as silicate and phosphate decreased As(V) adsorption efficiency. An increase temperature resulted a decrease in the amount of As(V) adsorbed by 6%. The continuous fixed bed column study showed that at the adsorbent bed depth of 30 cm and residence time of 168 min, the CRB was capable of treating 340 bed volumes of As(V) spiked water (C0 = 2 mg/L) before breakthrough (Ce = 0.01 mg/L). This solid adsorbent, although not reusable, can be considered for design of adsorption columns as an efficiency arsenic adsorption media.
Subject(s)
Aluminum Oxide/chemistry , Arsenic/chemistry , Calcium Carbonate/chemistry , Water Pollutants, Chemical/chemistry , Water Purification/methods , Water/chemistry , Adsorption , Humans , Hydrogen-Ion Concentration , Phosphates/chemistry , Silicates/chemistry , TemperatureABSTRACT
Steady-state experiments were conducted on arsenic (V) removal from contaminated groundwater using two different grades of bauxite ore. The materials considered were refractory grade bauxite (RB) with high alumina and low iron content and feed bauxite (FB) with moderate alumina and high iron content. Adsorption studies were carried out for different parameters such as pH, adsorbent dosage, As(V) concentration and reaction time to establish optimum conditions. RB was found to be the better adsorbent compared to FB with a maximum As(V) adsorption capacity of 1.49 mg As(V)/g compared to 1.26 mg As(V)/g of FB. Both the adsorbents showed similar type of behavior with varying magnitude. As(V) adsorption was independent of the ionic strength suggesting an inner-sphere surface complexion mechanism. The kinetics of the As(V) adsorption could be best explained by pseudo-second-order rate equation. The adsorption was found strongly pH dependent, with maximum adsorption over a wide range of pH approximately 4.0 to 7.5. The column study results showed that at a adsorbent bed depth of 30 cm and feed flow rate of 50 ml/h, the RB was capable of treating 256 bed volumes of As(V) contaminated water (Co=1.79 mg/L) before breakthrough (Ce=0.01 mg/L).
Subject(s)
Aluminum Oxide/chemistry , Arsenic/isolation & purification , Environmental Restoration and Remediation/methods , Water Pollutants, Chemical/isolation & purification , Adsorption , Diffusion , Hydrogen-Ion Concentration , KineticsABSTRACT
Spent catalyst generally contains valuable metals like Mo, Co, Ni on a supporting material, such as gamma-A1(2)O(3). In the present study, a two stage alkali/acid leaching process is proposed to selectively target molybdenum and cobalt/nickel separately to facilitate the downstream processing. Prior to the leaching, the spent catalyst was calcined at 500 degrees C to remove C and S; and to convert metal sulphides to metal oxides. 98% Mo, 93% Co and 90% Ni was effectively recovered by this process. The sulphuric acid leaching of spent catalyst, previously treated by alkali solutions to remove Mo, yielded a solution rich in Ni, Co and Al. In order to recover Co and Ni, the Al impurity must be eliminated. The extraction and stripping of Al has been carried out using the organo-phosphinic extractant, Cyanex 272 diluted in carbon tetrachloride. Quantitative Al extraction efficiency was achieved with 1.0M Cyanex 272 in two stages at an aqueous:organic (A:O) phase ratio of 1:1 and equilibrium pH of 3.2. Complete stripping of Al from the loaded organic was carried out using 2M H(2)SO(4) at an A:O phase ratio of 1:1. The extraction reaction proceeded via the cation exchange mechanism and the extracted species was assumed to be AlA(3).3HA. The extraction of Al was carried out in the presence of various ions to ascertain the tolerance limit of individual ions. The regenerated solvent was successfully used for 8 cycles without any significant loss of extraction efficiency, suggesting that Cyanex 272 is extremely stable under present experimental conditions.