Chemokines and cytokines: Axis and allies in prostate cancer pathogenesis.

Chemokines are recognized as the major contributor to various tumorigenesis, tumor heterogeneity, and failures of current cancer therapies. The tumor microenvironment (TME) is enriched with chemokines and cytokines and plays a pivotal role in cancer progression. Chronic inflammation is also considered an instructive process of cancer progression, where chemokines are spatiotemporally secreted by malignant cells and leukocyte subtypes that initiate cell trafficking into the TME. In various cancers, prostate cancer (PCa) is reported as one of the leading cancers in the worldwide male population. The chemokines-mediated signaling pathways are intensively involved in PCa progression and metastasis. Emerging evidence suggests that chemokines and cytokines are responsible for the pleiotropic actions in cancer, including the growth, angiogenesis, endothelial mesenchymal transition, leukocyte infiltration, and hormone escape for advanced PCa and therapy resistance. Chemokine's system and immune cells represent a promising target to suppress tumorigenic environments and serve as potential therapy/immunotherapy for the PCa. In this review, an attempt has been made to shed light on the alteration of chemokine and cytokine profiles during PCa progression and metastasis. We also discussed the recent findings of the diverse molecular signaling of these circulating chemokines and their corresponding receptors that could become future targets for therapeutic management of PCa.

Mechanism of phthalate esters in the progression and development of breast cancer.

Phthalate esters are produced widely for their use as plasticizer in consumer products such as cosmetics, PVC, deodorants etc. Their use is considered harmless but they are known to induce cancer and work as endocrine disruptors. In this review, we try to emphasize the ubiquitous presence of phthalate esters and the pathways they affect to induce, metastasizes cancer or to prompt drug resistance in cancer cells. We reviewed the literature from the last one decade on PubMed. The keywords used were 'Phthalates' 'Breast cancer' 'endocrine disruptors' 'environmental carcinogens' 'Phthalates and reproductive health' etc. In conclusion, the phthalates are able to mimic estrogen, to prompt proliferation, metastasis and drug resistance in breast cancer cells. The data for its dosage exposure to induce ill-effects remains largely inconsistent. The only well researched molecular target of phthalate is Aryl hydrocarbon receptor (AhR) which is a ligand activated transcription factor. Being an interesting and important problem of research this aspect had not been touched in the way as it has to be.

Differential levels of CHMP2B, LLPH, and SLC25A51 proteins in secondary renal amyloidosis.

OBJECTIVES: Renal amyloidosis (RA) is a rare disease, typically manifested with proteinuria, nephrotic syndrome, and ultimately leads to renal failure. The present study aims to profile the proteomes of renal amyloidosis patient's serum and healthy controls, along with relative quantification to find out robust markers for RA. METHODS: In this study, 12 RA patients and their corresponding age and gender-matched healthy controls were recruited from the Nephrology department of Max Super Specialty Hospital, New Delhi. We employed gel-based proteomic approach coupled with MALDI-TOF MS to compare protein expression patterns in RA patients and controls. Furthermore, validation of differential proteins (selected) was done using bio-layer interferometry. RESULTS: Eleven proteins showed remarkably altered expression levels. Moreover, expression modulation of three proteins (LLPH, SLC25A51, and CHMP2B) was validated which corroborated with two-dimensional gel electrophoresis (2-DE) results showing significant upregulation (p < 0.05) in RA patients followed by ROC analysis which demonstrated the diagnostic potential of these proteins. A protein-protein master network was generated implicating the above identified proteins along with their interactors, fishing out the routes leading to amyloidosis. CONCLUSION: This study indicates that the identified serum proteomic signatures could improve early diagnosis and lead to possible therapeutic targets in RA.

Mechanism of tumour microenvironment in the progression and development of oral cancer.

Oral cancer has been a major problem all across the globe, majorly in the developing countries. With a growing emphasis in the field of cancer research, the contribution of the tumour microenvironment has been gaining a lot of importance in identifying the role of components other than the tumour cells that cause the development of cancer, thus changing the outlook. The review will shed light on the studies that describe the role of microenvironment, its components as well as summarize the studies related to their mechanism in the progression of oral cancer. The literature for the review was derived mainly from Google Scholar and PubMed, in particular concentrating on the most recent papers published in 2019 and 2020, by using the keywords "Cancer, Oral Cancer, Metastasis, OSCC, Tumour microenvironment, CAFs, ECM, Cytokines, Hypoxia, Therapeutics targeting the microenvironment". The study provides insight into the world of micro-environmental regulation of oral cancer, the mechanism by which they interact and how to exploit it as a potential therapeutic haven for treating the disease. The components Cancer-Associated Fibroblasts (CAFs), Tumour-associated Macrophages (TAMs), Tumour-associated neutrophils (TANs), Hypoxic environment, myeloid-derived stem cells (MDSCs) and T regulatory (Tregs) cells and underlying mechanisms that control them will be the targets of study to understand the microenvironment.

Pre-clinical toxicity assessment of Artemisia absinthium extract-loaded polymeric nanoparticles associated with their oral administration.

Background: This study was designed to quantify the composition of the ethanolic extract of Artemisia absinthium through gas chromatography-mass spectrometry analysis and ensure in vivo safety of A. absinthium extract-loaded polymeric nanoparticles (ANPs) before considering their application as a drug carrier via the oral route. Methods: We synthesized N-isopropylacrylamide, N-vinyl pyrrolidone, and acrylic acid crosslinked polymeric NPs by free-radical polymerization reaction and characterized them by Fourier-transform infrared spectroscopy, transmission electron microscopy, and dynamic light scattering spectroscopy. Different concentrations of extract (50 mg/kg, 300 mg/kg, and 2,000 mg/kg body weight) were encapsulated into the hydrophobic core of polymeric micelles for the assessment of acute oral toxicity and their LD50 cut-off value as per the test procedure of OECD guideline 423. Orally administered female Wistar rats were observed for general appearance, behavioral changes, and mortality for the first 30 min, 4 h, 24 h, and then, daily once for 14 days. Result: ANPs at the dose of 300 mg/kg body weight were used as an initial dose, and rats showed few short-lived signs of toxicity, with few histological alterations in the kidney and intestine. Based on these observations, the next set of rats were treated at a lower dose of 50 mg/kg and a higher dose of 2,000 mg/kg ANPs. Rats administered with 50 mg/kg ANPs remained normal throughout the study with insignificant histological disintegration; however, rats treated at 2,000 mg/kg ANPs showed some signs of toxicity followed by mortality among all three rats within 24-36 h, affecting the intestine, liver, and kidney. There were no significant differences in hematological and biochemical parameters among rats treated at 50 mg/kg and 300 mg/kg ANPs. Conclusion: We conclude that the LD50 cut-off value of these ANPs will be 500 mg/kg extract loaded in polymeric NPs.

Evaluation of acute oral toxicity of Ipomoea turpethum extract loaded polymeric nanoparticles in Wistar rats.

Introduction: The amalgamation of novel drug delivery techniques and potential drugs is considered the most promising tool for the treatment of diseases. In our study, we have employed N-isopropyl acrylamide, N-vinyl pyrrolidone, and acrylic acid (NIPAAM-VP-AA) copolymeric nanoparticles for delivering Ipomoea turpethum root extract. I. turpethum is a perennial herb (Convolvulaceae family) and has been used as medicine for ages. The present study was conducted to evaluate the safety of I. turpethum root extract-loaded NIPAAM-VP-AA polymeric nanoparticles (NVA-IT) in Wistar rats. Methods: An acute oral toxicity study was conducted in accordance with OECD guidelines 423 for the testing of chemicals. Different doses of NVA-IT i.e., 5 mg/kg, 50 mg/kg, 300 mg/kg, and 2000 mg/kg were administered to female Wistar rats in a stepwise manner using oral gavage. The toxicity signs were thoroughly observed for the next 14 days. At the end of the study, the blood and vital organs were harvested for hematological, biochemical, and histopathological studies. Result: No mortality or pathological anomalies were observed even at the highest dose which exemplifies that the lethal dose would be more than 2000 mg/kg body weight (GSH category 5). Behavioral changes, biochemical parameters, and histopathology of vital organs were normal after NVA-IT administration. Conclusion: This study demonstrated that NVA-IT nanoparticles are non-toxic and can be considered for therapeutic use in different diseases, such as inflammation, CNS diseases, Cancer, etc.

Secretome analysis of breast cancer cells to identify potential target proteins of Ipomoea turpethum extract-loaded nanoparticles in the tumor microenvironment.

Background: Breast cancer is the leading cause of frequent malignancy and morbidity among women across the globe, with an increment of 0.5% incidences every year. The deleterious effects of traditional treatment on off-target surrounding cells make it difficult to win the battle against breast cancer. Hence, an advancement in the therapeutic approach is crucial. Nanotechnology is one of the emerging methods for precise, targeted, and efficient drug delivery in cells. The previous study has demonstrated the cytotoxic effect of Ipomoea turpethum extract on breast cancer cells delivered via NIPAAM-VP-AA nanoparticles (NVA-IT). Manipulating the tumor microenvironment (TME) to inhibit cancer progression, invasion, and metastasis seems to be very insightful for researchers these days. With the help of secretome analysis of breast cancer cells after treatment with NVA-IT, we have tried to find out the possible TME manipulation achieved to favor a better prognosis of the disease. Method: MCF-7 and MDA MB-231 cells were treated with the IC50 value of NVA-IT, and the medium was separated from the cells after 24 h of the treatment. Nano LCMS/MS analysis was performed to identify the secretory proteins in the media. Further bioinformatics tools like GENT2, GSCA, GeneCodis 4, and STRING were used to identify the key proteins and their interactions. Result: From the nano LCMS/MS analysis, 70 differentially expressed secretory proteins in MCF-7 and 191 in MDA MB-231 were identified in the cell's media. Fifteen key target proteins were filtered using bioinformatics analysis, and the interaction of proteins involved in vesicular trafficking, cell cycle checkpoints, and oxidative stress-related proteins was prominent. Conclusion: This study concluded that I. turpethum extract-loaded NIPAAM-VP-AA nanoparticles alter the secretory proteins constituting the TME to cease cancer cell growth and metastasis.

Secretome profiling of Artemisia absinthium extract-loaded polymeric nanoparticle-treated MCF-7 and MDA-MB-231 revealed perturbation in microtubule assembly and cell migration.

Introduction: Artemisia absinthium (wormwood) exhibits anticancer properties by inhibiting proliferation and causing cell death in breast cancer. Targeted drug delivery of A. absinthium nanoformulation using N-isopropyl acrylamide, N-vinyl pyrrolidone, and acrylic acid-based polymeric nanoparticles (NVA-AA NPs) was ensured by utilizing features of the tumor microenvironment, although their mechanism of action involved in cytotoxicity remains unknown. Methods: The present study employed nano LC-MS/MS to identify differences in secretory protein expression associated with the treatment of breast cancer cell lines (MCF-7; MDA-MB-231) by NVA-AA NPs for the determination of affected pathways and easily accessible therapeutic targets. Different bioinformatics tools were used to identify signature differentially expressed proteins (DEPs) using survival analysis by GENT2 and correlation analysis between their mRNA expressions and sensitivity toward small-molecule drugs as well as immune cell infiltration by GSCA. Results: Analysis by GENT2 revealed 22 signature DEPs with the most significant change in their expression regulation, namely, gelsolin, alpha-fetoprotein, complement component C3, C7, histone H2B type 1-K, histone H2A.Z, H2AX, heat shock cognate 71 kDa protein, heat shock 70 kDa protein 1-like, cytochrome c somatic, GTP-binding nuclear protein Ran, tubulin beta chain, tubulin alpha-1B chain, tubulin alpha-1C chain, phosphoglycerate mutase 1, kininogen 1, carboxypeptidase N catalytic chain, fibulin-1, peroxiredoxins 4, lactate dehydrogenase C, SPARC, and SPARC-like protein 1. Correlation analysis between their mRNA expressions versus immune cell infiltrates showed a positive correlation with antitumor immune response elicited by these NPs as well as a correlation with drug response shown by the GDSC and CTRP drugs in different cancer cells. Discussion: Our results suggest that NVA-AA NPs were able to invade the tumor microenvironment; transformed the communication network between the cancer cells; affected potential drivers of microtubular integrity, nucleosome assembly, and cell cycle; and eventually caused cell death.

Maternal Embryonic Leucine Zipper Kinase is Associated with Metastasis in Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) has high relapse and metastasis rates and a high proportion of cancer stem-like cells (CSC), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, is known to promote CSC maintenance and malignant transformation. However, the role of MELK in TNBC metastasis is unknown; we sought to address this in the current study. We found that MELK mRNA levels were higher in TNBC tumors [8.11 (3.79-10.95)] than in HR+HER2- tumors [6.54 (2.90-9.26)]; P < 0.001]. In univariate analysis, patients with breast cancer with high-MELK-expressing tumors had worse overall survival (P < 0.001) and distant metastasis-free survival (P < 0.01) than patients with low-MELK-expressing tumors. In a multicovariate Cox regression model, high MELK expression was associated with shorter overall survival after adjusting for other baseline risk factors. MELK knockdown using siRNA or MELK inhibition using the MELK inhibitor MELK-In-17 significantly reduced invasiveness, reversed epithelial-to-mesenchymal transition, and reduced CSC self-renewal and maintenance in TNBC cells. Nude mice injected with CRISPR MELK-knockout MDA-MB-231 cells exhibited suppression of lung metastasis and improved overall survival compared with mice injected with control cells (P < 0.05). Furthermore, MELK-In-17 suppressed 4T1 tumor growth in syngeneic BALB/c mice (P < 0.001). Our findings indicate that MELK supports metastasis by promoting epithelial-to-mesenchymal transition and the CSC phenotype in TNBC. Significance: These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.

Herbal Based Polymeric Nanoparticles as a Therapeutic Remedy for Breast Cancer.

BACKGROUND: The currently available anti breast cancer agents as well as conventional drug delivery methods have some limitations. OBJECTIVE: In view of these limitations, researchers used phytochemicals/herbal extracts as anti-breast cancer agents together with the polymeric nanoparticles to provide an effective way of targeted drug delivery with lesser /no side effects. METHODS: The literature for this review was searched during the year 2015 to 2019, using the keywords, ' 'breast cancer', 'breast cancer and its current treatments', 'plants against the breast cancer', 'polymeric nanoparticles', 'herbal based polymeric nanoparticles'. The databases i.e., PubMed, Science Direct, and Google Scholar, were used for collecting the information. RESULTS: In the present review, an attempt was made to summarize the potential of herbal-based nanoformulation as a specific and high efficacy therapeutic strategy in order to pave the way for future research involving screening and use of herbal nanoparticles for the treatment of breast cancer. CONCLUSION: The encapsulation of the herbal extract in the polymeric nanoparticles is the prominent, effective, and emerging way of targeted drug delivery for cancer. It may serve as a safer way of targeted drug delivery and maybe the answer to the complications related to the currently available anti-breast cancer agents as well as limitations of the conventional method of drug delivery.

Mechanism of WASP and WAVE family proteins in the progression of prostate cancer.

Prostate cancer (PCa) is the second most commonly diagnosed and third lethal cause of death from cancer in men worldwide. Despite the availability of vast treatment procedures, still the high occurrence of invasion and metastasis of PCa are reported in cancer patients. The WASP (Wiskott-Aldrich syndrome protein) and WAVE (WASP family verprolin homologous protein) family of proteins are actin cytoskeleton regulatory proteins, reported to enhance cancer cell invasion and migration in prostate cancer. Hence, this review sheds light on the studies that explored the potential role of WASP and WAVE family of proteins in invasion and metastasis of prostate cancer. The research articles explored for the completion of this review were mostly from PubMed and Google Scholar by using the appropriate keywords for indexing. The conserved function of WASP and WAVE protein family is to receive the upstream signals from the Rho GTPase family and transmit them to activate the Arp2/3 complex that leads to rapid actin polymerization at leading edge of cells, which is crucial for PCa metastasis. Therefore, targeting these proteins could reflect a very interesting therapeutic opportunity to combat prostate cancer.

Exosome vesicle as a nano-therapeutic carrier for breast cancer.

Breast cancer (BC) is one of the most common lethal diseases found in women; in which shortcomings of currently used treatment procedures and efficiency to target disease contribute to the increment in mortality. Despite other factors, exosomes, a major class of EVs (extracellular vesicles) also play a regulatory role in normal physiological processes and have a major function in proliferation, metastases, and resistance in BC. Interestingly, despite their role in the progression of BC, exosomes also showed their importance as a drug carrier in the targeted drug delivery. The present review aims to shed light on the role of exosomes as a potential nano-therapeutic vehicle in the targeted drug delivery for BC. Information for this review was searched from PubMed and Google Scholar mostly during the year 2019-2020 by using appropriate keywords. The exosomes have been efficiently used in cancer therapeutics where these nano vehicles having specific markers help in efficient targeted delivery of therapeutics including proteins, nucleic acid, and anti-cancer drugs to BC cells. The properties of exosomes as an efficient delivery system can be explored in the future and holds the potential to be used in other forms of cancer as well.

COVID-19 Threat to the World: Current and Possible Diagnostic/Treatment Strategies.

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a world-wide crisis. To contain the virus, it is important to find infected individuals and isolate them to stop transmission. Various diagnostic techniques are used to check for infection. With the havoc that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has created, it is imperative to work on alternative diagnostic techniques that can be used at both point of care with little or no expertise and at mass testing (i.e., when screening). Despite extensive research, to this date no specific effective treatment or cure is available to neutralize this viral infection. Globally, researchers are working to develop effective treatments, and several vaccines have been approved for public use. We found the studies that we explored for this review using appropriate key words for indexing in PubMed and Google Scholar from 2019 to 2020. We compile various techniques that have been used worldwide to diagnose and treat SARS-CoV-2 and discuss novel methods that may be modified for use in diagnosis and treatment. It is crucial to develop a more specific serological test for diagnosis that can rule out the possibility of COVID-19 and be used for mass testing. An affordable, safe, targeted, effective treatment must be developed to cure this disease, which has created a public health emergency of international concern.

Evaluation of Cytotoxicity of Different Part Extracts of Ipomoea turpethum against Breast Cancer Cell Lines.

The aim of the present study was to explore the anti-breast cancer activity of the plant I. turpethum together with the comparative analysis of the cytotoxicity of the extracts from different parts of the plant. The gas chromatography-mass spectrometry (GC-MS) analysis of the plant revealed the identification of 71 compounds. The cytotoxicity of the extracts from different parts (whole, aerial, and root) of the plant was evaluated against the breast cancer cell lines (MCF-7 and MDA MB-231) by 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The findings of these assays were further confirmed by the carboxyfluorescein diacetate succinimidyl ester (CFSE) proliferation assay, DAPI (4',6-diamidino-2-phenylindole) nuclear staining, and simple microscopy images. The results of the MTT assay revealed that the root extract showed the lowest IC50 values, i.e., 516 µg/mL for MCF-7 and 396 µg/mL for MDA MB-231 cell lines. The LDH release in the medium was high in the root extract treated cells, i.e., 28.87% for MCF-7 and 23.62% for MDA MB-231 cell lines. Moreover, the CFSE proliferation assay also showed the decrease in the proliferation of the cells up to 48.7% and 46.4% in case of MCF-7 and MDA MB-231 cells, respectively. The fragmented and condensed nuclear material in both the cell lines was observed in the DAPI nuclear staining. In conclusion, results showed that the root extract possess the highest cytotoxicity among all other tested extracts toward both breast cancer cell lines (MCF-7 and MDA MB-231).

Cytotoxic potential of Artemisia absinthium extract loaded polymeric nanoparticles against breast cancer cells: Insight into the protein targets.

Targeted drug delivery system in the form of herbal based nano-formulations is the new ray of hope for minimizing the side effects related to the anti-cancer drugs as well as conventional drug delivery system. In view of this, the present study was designed to evaluate the cytotoxic potential of A. absinthium extract loaded polymeric nanoparticles (NVA-AA) against the breast cancer cell lines (MCF-7 and MDA MB-231) and to identify the protein targets for the caused cytotoxicity. The polymeric nanoparticles (PNPs) were prepared by free radical mechanism and loaded with the whole plant extract. The cytotoxicity of these NVA-AA were evaluated on the breast cancer cell lines via different cytotoxic parameters viz. MTT assay, CFSE proliferation assay, apoptosis assay, cell cycle study. The protein targets and the interaction among them were identified by nano-LCMS/MS analysis and STRING online tool respectively, which were further validated by qPCR and BLI. The LCMS/MS analysis suggests that the caused cytotoxicity was due to the alteration of proteins involved in vesicular trafficking, apoptosis, proliferation and metastasis. Further, interactome analysis identified UBA52 in MCF-7 and TIAL1, PPP1CC in MDA MB-231 cells as the central molecule in the vesicular trafficking and apoptosis networking connection.

Vesicular trafficking-related proteins as the potential therapeutic target for breast cancer.

Vesicular trafficking between endoplasmic reticulum and Golgi plays a major role in the growth and proliferation of breast cancer cells. Various proteins regulate this ER-Golgi kinetics; however, their potential as therapeutic targets in breast cancer has not been much evaluated. In the present review, we try to shed light on the implication of vesicular trafficking-related proteins like Rab family of proteins, in the pathogenesis of breast cancer via promoting cancer cell proliferation and invasion. The literature for this review was mainly searched in PubMed during the years 2014 to 2018 by using the keywords, 'breast cancer', 'breast cancer and its current treatments', 'breast cancer and vesicular trafficking', 'Rab family proteins in breast cancer', etc. Targeting proteins involved in vesicular transport like Rab GTPases, the neural precursor cell-expressed developmentally downregulated protein 9 (NEDD9), runt-related transcription factor 2 (RUNX2), human rhomboid family-1 (RHBDF1), monocarboxylate transporter 4, etc., would aid in designing improved therapeutics for the treatment of breast cancer.

Correction: Identification of protein targets and the mechanism of the cytotoxic action of Ipomoea turpethum extract loaded nanoparticles against breast cancer cells.

Correction for 'Identification of protein targets and the mechanism of the cytotoxic action of Ipomoea turpethum extract loaded nanoparticles against breast cancer cells' by Mohd Mughees et al., J. Mater. Chem. B, 2019, 7, 6048-6063.

Identification of protein targets and the mechanism of the cytotoxic action of Ipomoea turpethum extract loaded nanoparticles against breast cancer cells.

The shortcomings of the currently available anti-breast cancer agents compel the development of the safer targeted drug delivery for the treatment of breast cancer. The aim of the present study was to evaluate the anti-breast cancer potential of Ipomoea turpethum extract loaded nanoparticles (NIPAAM-VP-AA) against breast cancer, together with the identification of the key proteins responsible for the caused cytotoxicity. For this, we explored the tumor microenvironment for targeted drug delivery and synthesized (temperature and pH responsive) double triggered polymeric nanoparticles by the free radical mechanism and characterized them by DLS and TEM. The extract which emerged as the best extract, i.e. root extract, was loaded on the nanoparticles and the cytotoxicity was evaluated in breast cancer cell lines (MCF-7 and MDA-MB-231) by various cytotoxic assays like MTT assay, CFSE cell proliferation assay, apoptosis assay, cell cycle study and DAPI nuclear staining. The key protein targets responsible for the caused cytotoxicity were identified by nano-LC-MS/MS analysis. The proteome analysis revealed that most of the significantly differentially expressed proteins have a role in proliferation, vesicular trafficking, apoptosis and tumor suppression. Finally, the interaction among the highly differentially expressed proteins was identified by using the STRING online tool, which showed that I. turpethum nanoparticles caused apoptosis in MCF-7 and MDA MB-231 cells by targeting nucleolysin TIAR, serine/threonine-protein phosphatase PP1 and ubiquitin-60S ribosomal protein L40.