ResearchPad - Pharmaceutical Science https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Gallic Acid Impedes Non-Small Cell Lung Cancer Progression via Suppression of EGFR-Dependent CARM1-PELP1 Complex]]> https://www.researchpad.co/product?articleinfo=N1b23bc24-670a-43db-a66c-d8a2ae305fb9

Background

Non-small cell lung cancer (NSCLC) is a common cause of cancer-related deaths. This study identified the regulatory pattern of gallic acid in NSCLC.

Methods

Human NSCLC cells were treated with different doses of gallic acid, after which, MTT assay and flow cytometry were performed to determine the survival and apoptotic rate of human NSCLC cells. Then, co-immunoprecipitation assay was performed to analyze the relationships between gallic acid, epidermal growth factor receptor (EGFR), and CARM1-PELP1. Next, we analyzed whether PELP1, CARM1 and EGFR were associated with the effects of gallic acid on NSCLC cells by conducting rescue experiments. The expression pattern of phosphorylated EGFR, EGFR, Ki67, as well as Fas, FasL and Caspase 3 proteins in cancer cells or xenografts was measured by Western blot analysis. Lastly, the role of gallic acid in the tumor growth was assessed in nude mice.

Results

The ideal dose of gallic acid that presented good suppressive effect on NSCLC cells were 30 μM, 50 μM and 75 μM, respectively. Gallic acid played an inhibiting role in the activation of EGFR, which further reduced the formation of CARM1-PELP1 complex, ultimately repressed the proliferation and elevated apoptosis of NSCLC cells. Meanwhile, CARM1 repression led to decreased growth, proliferation and migration abilities of NSCLC cells. Animal experiments confirmed that gallic acid contributed to the inhibition of tumor growth in vivo.

Conclusion

To sum up, gallic acid could potentially prevent NSCLC progression via inhibition of EGFR activation and impairment of the binding of CARM1 to PELP1, highlighting a novel therapy to dampen NSCLC progression.

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<![CDATA[In vitro Multistage Malaria Transmission Blocking Activity of Selected Malaria Box Compounds]]> https://www.researchpad.co/product?articleinfo=N33dbfc47-3e99-40b1-8df9-cdee7f2bea3a

Purpose

Continuous efforts into the discovery and development of new antimalarials are required to face the emerging resistance of the parasite to available treatments. Thus, new effective drugs, ideally able to inhibit the Plasmodium life-cycle stages that cause the disease as well as those responsible for its transmission, are needed. Eight compounds from the Medicines for Malaria Venture (MMV) Malaria Box, potentially interfering with the parasite polyamine biosynthesis were selected and assessed in vitro for activity against malaria transmissible stages, namely mature gametocytes and early sporogonic stages.

Methods

Compound activity against asexual blood stages of chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of Plasmodium falciparum was tested measuring the parasite lactate dehydrogenase activity. The gametocytocidal effect was determined against the P. falciparum 3D7elo1-pfs16-CBG99 strain with a luminescent method. The murine P. berghei CTRP.GFP strain was employed to assess compounds activities against early sporogonic stage development in an in vitro assay simulating mosquito midgut conditions.

Results

Among the eight tested molecules, MMV000642, MMV000662 and MMV006429, containing a 1,2,3,4-tetrahydroisoquinoline-4-carboxamide chemical skeleton substituted at N-2, C-3 and C-4, displayed multi-stage activity. Activity against asexual blood stages of both strains was confirmed with values of IC50 (50% inhibitory concentration) in the range of 0.07–0.13 µM. They were also active against mature stage V gametocytes with IC50 values below 5 µM (range: 3.43–4.42 µM). These molecules exhibited moderate effects on early sporogonic stage development, displaying IC50 values between 20 and 40 µM.

Conclusion

Given the multi-stage, transmission-blocking profiles of MMV000642, MMV000662, MMV006429, and their chemical characteristics, these compounds can be considered worthy for further optimisation toward a TCP5 or TCP6 target product profile proposed by MMV for transmission-blocking antimalarials.

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<![CDATA[Data of ureagenesis from ammonia, glutamine and alanine, and mitochondrial aquaporin-8 expression in thioacetamide-treated hepatocytes]]> https://www.researchpad.co/product?articleinfo=N31bbd1ba-207b-4380-9fa0-013b26ff2dd3

We present data about the synthesis of urea from different substrates, i.e., free ammonia, glutamine and alanine in primary cultured rat hepatocytes treated or untreated with the model hepatotoxic agent thioacetamide (TAA). We also provide data about the expression of mitochondrial aquaporin-8 (mtAQP8), a hepatocyte channel protein which facilitates ammonia diffusion into mitochondria to supply the urea cycle. Ammonia-derived ureagenesis was significantly inhibited by about 30% while that from the both amino acids resulted unaffected in TAA-treated hepatocytes. Protein expression of mtAQP8 was decreased by about 80% after TAA treatment. These data can be useful for the understanding of the mechanisms of drug-induced hepatic dysfunction.

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<![CDATA[Pipeline for the removal of hardware related artifacts and background noise for Raman spectroscopy]]> https://www.researchpad.co/product?articleinfo=N62784fe2-635a-4b82-912b-cad3436d7cd3

Raman spectroscopy is a real-time, non-contact, and non-destructive technique able to obtain information about the composition of materials, chemicals, and mixtures. It uses the energy transfer properties of molecules to detect the composition of matter. Raman spectroscopy is mainly used in the chemical field because background fluorescence and instrumental noise affect biological (in vitro and in vivo) measurements. In this method, we describe how hardware related artifacts and fluorescence background can be corrected without affecting signal of the measurement. First, we applied manual correction for cosmic ray spikes, followed by automated correction to reduce fluorescence and hardware related artifacts based on a partial 5th degree polynomial fitting and Tophat correction. Along with this manuscript we provide a MatLab script for the automated correction of Raman spectra.

  • Polynomial_Tophat_background_subtraction _methods.m” offers an automated method for the removal of hardware related artifacts and fluorescence signals in Raman spectra.

  • Polynomial_Tophat_background_subtraction _methods.m” provides a modifiable MatLab file adjustable for multipurpose spectroscopy analysis.

  • We offer a standardized method for Raman spectra processing suitable for biological and chemical applications for modular confocal Raman spectroscopes.

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<![CDATA[Data on the characterization of a platelet lysate and of the system in which it is included (nanoparticles/hydrogel), intended for the treatment of wounds]]> https://www.researchpad.co/product?articleinfo=N504cd2b6-9397-45c1-ae32-998fb84e4713

Platelet lysate has attracted attention for different biomedical applications, including biological processes where cellular proliferation and migration have been altered. Spectroscopic properties of a platelet lysate obtained from human platelets were performed in order to be incorporated in polymeric nanoparticles and then into a Pluronic F127 hydrogel, intended for wound healing (more details can be found at https://doi.org/10.1016/j.ejps.2020.105231 [1]). The platelet lysate (PL) was assessed by ultraviolet, infrared and circular dichroism spectroscopy. The developed hydrogel was also analyzed by infrared spectroscopy to evaluate if the Pluronic F127 structure was maintained when the nanoparticles or platelet lysate-loaded nanoparticles were included. The sol-gel transition temperature of the hydrogel was determined through its thermal behavior and by dynamic light scattering.

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<![CDATA[A novel method for the collection of highly developmental murine immature oocytes]]> https://www.researchpad.co/product?articleinfo=N2cfb2892-63b5-43ce-982e-b341a580758c

Isolation of germinal vesicle (GV) or metaphase I (MI) oocytes from large antral follicles, using a 30 gauge needle, in mice is a common method for the retrieval of immature oocytes from ovaries. However, this method depends entirely on the experience and judgment of the investigator. It is possible that not all of the isolated immature oocytes are from large antral follicles nor necessarily represent the cohort of oocytes that would be perfectly developed and consequently ovulated upon hormonal stimulation. Here, we administered an FDA approved phosphodiesterase 3A inhibitor, named cilostazol, in superovulated mice to result in the ovulation of GV or MI oocytes, depending on time and frequency of administration. The presented method results in mice ovulating GV or MI oocytes, which can be recovered from the oviduct without the investigator's judgment mentioned above. This method does not only result in immature oocytes with high yield, health, synchronized maturation, and competence levels but also is time and labor efficient. It also permits for physiological selections of a cohort of immature oocytes that would be entirely developed and eventually ovulated, as opposed to the conventional method.

  • Complete superovulation

  • Administration of cilostazol at different times

  • Recovery of ovulated immature oocytes from oviducts

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<![CDATA[Data on the stability of darunavir/cobicistat suspension after tablet manipulation]]> https://www.researchpad.co/product?articleinfo=Nb07c557b-e791-4fd2-8ef9-697b722fc19b

The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. In the absence of authorised pharmacological treatments, many antiretrovirals, including darunavir/cobicistat fixed combination, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortunately, for most of them, the drug products available on the market are not designed to be administered by a nasogastric tube to inpatients of intensive care units. Therefore, their manipulation, even if it can strongly affect the product quality, is necessary for the preparation of suspension to meet patients’ need. In this situation, it is urgent to provide data and guidance to support hospital pharmacists and clinicians in their activity. The data in this article indicate that darunavir/cobicistat suspensions compounded by pharmacists using as active ingredient a commercially available tablet can be stable at least for one week.

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<![CDATA[Secondary prevention of acute coronary syndrome with antiplatelet agents in real life: A high-dimensional propensity score matched cohort study in the French National claims database]]> https://www.researchpad.co/product?articleinfo=N40eff8b8-f258-43ec-82a3-f4c81c576861

Graphical abstract

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<![CDATA[Data on metabolic stability, aqueous solubility and CYP inhibition of novel triazole-based nicotinamide phosphoribosyltransferase (NAMPT) inhibitors]]> https://www.researchpad.co/product?articleinfo=N60ba1e8b-af71-45b3-ab92-d5cb2dc5e5e0

In the related research article, entitled “Identification of novel triazole-based nicotinamide phosphoribosyltransferase (NAMPT) inhibitors endowed with antiproliferative and antiinflammatory activity” [1], we reported the in vitro hepatic metabolism data for compounds 30c, 48b, and 31b (here named as E5, A6, and T1), in comparison with the reference compounds GPP78 and FK866 [1–3]. In this article, we retrieved the available data about the hepatic microsomal stability and metabolites structural characterization of the entire library of triazole-based NAMPT inhibitors, also implementing the given information with data regarding aqueous solubility and CYP inhibition. Compounds are divided in subclasses based on the hydrolytic resistant groups replacing the amide function of GPP78 [1, 2].

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<![CDATA[The method simulating spontaneous pain in patients with nociplastic pain using rats with fibromyalgia-like condition]]> https://www.researchpad.co/product?articleinfo=N7b23d9d7-4da4-4ec5-a86b-1cd7d92bc21e

The method shown in this article simulates spontaneous pain in patients with nociplastic pain using rats; the measurement with this method could be related to better translation of analgesic efficacies of therapeutic compounds between rats and humans. Nociplastic pain occurs in various disorders including fibromyalgia. Because the pain in patients occurs without an external stimulus, we assessed spontaneous pain in rats. The grimace scale, a methodology for rating facial expression, has been used for measuring spontaneous pain in animals. However, the responses in animals have been rather short-lived, and the scale has never been applied to animals exhibiting nociplastic pain. Here, we apply the rat grimace scale (RGS) to the reserpine-induced fibromyalgia-like rat, which induces nociplastic pain. The ratings of the orbital tightening, nose/cheek flattening, and changes in characteristics of ears and whiskers by three raters, who were blinded to the treatment allocated to rats, demonstrated substantial, long-lasting change in facial expression of rats. In this article, reference images for raters, and sample images used for rater training are provided. All raters independently indicated that the RGS score is significantly elevated with this methodology in reserpine-induced fibromyalgia-like rats.

  • The grimace scale, a method for rating facial expression, is applied to the reserpine-induced fibromyalgia-like rat, which manifests nociplastic pain.

  • Facial expression change in the reserpine-induced fibromyalgia-like rat is substantial and long-lasting.

  • Elevation of the RGS score in the reserpine-induced fibromyalgia-like rat may simulate spontaneous pain in patients with nociplastic pain.

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<![CDATA[Data on GC-MS analysis, in vitro anti-oxidant and anti-microbial activity of the Catharanthus roseus and Moringa oleifera leaf extracts]]> https://www.researchpad.co/product?articleinfo=N6a38c90d-0037-4102-b25f-966a2cdd83eb

The article reports data on chemical profiling by gas chromatography-mass spectrometry (GC-MS) of aqueous and methanolic leaf extracts of Madagascar periwinkle (Catharanthus roseus) and drumstick tree (Moringa oleifera) and on their antioxidant and antibacterial effects against three clinical human pathogens. In total 105 compounds were tentatively identified; in which 65 in Catharanthus roseus and 40 in Moringa oleifera compounds. A large number of peaks with good area percentage was found in methanolic extract of Catharanthus roseus with core chemical constituents such as trans-squalene, n-hexadecanoic acid, Eicosyl acetate, stearin, 1H-Benz(G)indole-3-carboxylic acid. The corresponding constituents from Moringa oleifera include 9-Octadecenoic acid (z)-, Heptadecanoic acid and phytol acetate. The highest scavenging activity (87.7% at 200 μg/mL) was shown by DPPH aqueous leaf extract of C. roseus. Moreover, the methanolic scavenging of both plant extracts was in the order of FRAP>DPPH>NO> H2O2 with lowest antioxidant activity (51.4% at 200 μg/mL) exposed by Catharanthus roseus in comparison of all cases. Good antibacterial action was examined against three different organisms (E.coli, B. subtilis and S. aureus) of aqueous infusion of Catharanthus roseus.

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<![CDATA[A method to dissolve 3-MCPD mono- and di-esters in aqueous cell culture media]]> https://www.researchpad.co/product?articleinfo=N845aa6e8-ad45-4619-a30e-ca25563e4888

Graphical abstract

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<![CDATA[Protocol for evaluating the abilities of diverse nitroaromatic prodrug metabolites to exit a model Gram negative bacterial vector]]> https://www.researchpad.co/product?articleinfo=N3dad3f2d-00d1-4f45-af16-275f5285761b

Graphical abstract

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<![CDATA[The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo]]> https://www.researchpad.co/product?articleinfo=5b59b9f1463d7e79e6a1004f

Cytochrome (CYP) 450 isoenzymes are the basic enzymes involved in Phase I biotransformation. The most important role in biotransformation belongs to CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2. Inhibition and induction of CYP isoenzymes caused by drugs are important and clinically relevant pharmacokinetic mechanisms of drug interaction. Investigation of the activity of CYP isoenzymes by using phenotyping methods (such as the determination of the concentration of specific substrates and metabolites in biological fluids) during drug administration provides the prediction of negative side effects caused by drug interaction. In clinical practice, the process of phenotyping of CYP isoenzymes and some endogenous substrates in the ratio of cortisol to 6β-hydroxycortisol in urine for the evaluation of CYP3A4 activity has been deemed to be a quite promising, safe and minimally invasive method for patients nowadays.

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<![CDATA[A Decision Support Tool Facilitating Medicine Design for Optimal Acceptability in The Older Population]]> https://www.researchpad.co/product?articleinfo=5b59793f463d7e5ce270da2e

Purpose

Medicine acceptability, which is of the utmost importance for vulnerable patients’ adherence, is driven by both user and product characteristics. Herein, a novel multivariate approach integrating the many aspects of acceptability is used to discriminate positively and negatively accepted medicines in the older population.

Methods

An observational study was carried out in eight hospitals and eight nursing homes to collect a large set of real-life data on medicines uses in older patients (≥65 years). Mapping and clustering explored these multiple observational measures and summarised the main information into an intelligible reference framework. Resampling statistics were used to validate the model’s reliability.

Results

A three-dimensional map and two clusters defining acceptability profiles, as positive or negative, emerged from the 1079 evaluations. Factors of interest (medicines, user features…) were positioned on the map at the barycentre of their evaluations and assigned to an acceptability profile. Focusing on patients’ ability to swallow, we have highlighted the tool’s efficacy in demonstrating the impact of user features on medicine acceptability.

Conclusions

This multivariate approach provides a relevant judgement criterion for this multi-dimensional concept. Facilitating the choice of the most appropriate dosage form to achieve optimal acceptability in a targeted population, this tool is of real potential to improve clinical decisions.

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<![CDATA[Combination of Garcinia cambogia Extract and Pear Pomace Extract Additively Suppresses Adipogenesis and Enhances Lipolysis in 3T3-L1 Cells]]> https://www.researchpad.co/product?articleinfo=5b591ff2463d7e56f0caf901

Background:

Inhibition of adipogenesis has been a therapeutic target for reducing obesity and obesity-related disorders such as diabetes, hypertension, atherosclerosis, and cancer. For decades, anti-adipogenic potential of many herbal extracts has been investigated. One example is Garcinia cambogia extract (GE) containing (-)-hydroxycitric acid as an active ingredient. GE is currently marketed as a weight loss supplement, used alone or with other ingredients. Pear pomace extract (PE), another natural product, has been also shown to have anti-adipogenic activity in a recent report.

Objective:

It was tested if the mixture of PE and GE (MIX) would produce more effective anti-adipogenic activity than PE or GE alone.

Materials and Methods:

Differentiation of 3T3-L1 preadipocyte was induced by adding insulin, dexamethasone, and isobutylmethylxanthine and lipid accumulation was measured by Oil Red O staining. Cellular markers for adipogenesis and lipolysis such as CCAAT/enhancer binding protein (C/EBP-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), fatty acid synthase (FAS), and hormone-sensitive lipase (HSL) was measured using immunocytochemistry.

Results:

MIX, compared to PE or GE alone, showed greater inhibition of lipid accumulation. Furthermore, MIX reduced the expression of adipogenesis-related factors C/EBP-α, PPAR-γ, and FAS more than PE or GE alone did. In contrast, the expression of HSL the enzyme required for lipolysis was further enhanced in MIX-treated adipocytes compared to the PE or GE alone treated groups.

Conclusions:

Anti-adipogenic effect of PE and GE appears synergistic, and the MIX may be a useful therapeutic combination for the treatment of obesity and obesity-related diseases.

SUMMARY

  • PE and GE efficiently inhibited adipocyte differentiation by suppressing the expression of adipogenic transcription factor CEBP-α and PPAR-γ.

  • PE and GE significantly decreased the expression of adipogenic enzyme FAS.

  • PE and GE increased the expression of lipid degrading enzyme HSL.

  • Mixture of PE and GE exhibited additive or moderately synergistic effect on adipocyte differentiation and lipid accumulation.

Abbreviations used: CEBP-a: CCAT/enhancer binding protein alpha, CI: Combination Index, FAS: Fatty acid synthase, GE: Garcinia cambogia extract, HSL: Hormone sensitive lipase, PE: Pear pomace extract, PPAR-γ: Peroxisome proliferator-activated receptor gamma.

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<![CDATA[PEGylated crushed gold shell-radiolabeled core nanoballs for in vivo tumor imaging with dual positron emission tomography and Cerenkov luminescent imaging]]> https://www.researchpad.co/product?articleinfo=5b58ec17463d7e5414116038

Background

Radioactive isotope-labeled gold nanomaterials have potential biomedical applications. Here, we report the synthesis and characterization of PEGylated crushed gold shell-radioactive iodide-124-labeled gold core nanoballs (PEG-124I-Au@AuCBs) for in vivo tumor imaging applications through combined positron emission tomography and Cerenkov luminescent imaging (PET/CLI).

Results

PEG-124I-Au@AuCBs showed high stability and sensitivity in various pH solutions, serum, and in vivo conditions and were not toxic to tested cells. Combined PET/CLI clearly revealed tumor lesions at 1 h after injection of particles, and both signals remained visible in tumor lesions at 24 h, consistent with the biodistribution results.

Conclusion

Taken together, the data provided strong evidence for the application of PEG-124I-Au@AuCBs as promising imaging agents in nuclear medicine imaging of various biological systems, particularly in cancer diagnosis.

Electronic supplementary material

The online version of this article (10.1186/s12951-018-0366-x) contains supplementary material, which is available to authorized users.

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<![CDATA[Development and Validation of an UPLC-MS/MS Method for Pharmacokinetic Comparison of Five Alkaloids from JinQi Jiangtang Tablets and Its Monarch Drug Coptidis Rhizoma]]> https://www.researchpad.co/product?articleinfo=5b4cd630463d7e0fba429dfa

JinQi Jiangtang (JQJT) tablets, a Chinese patent medicine approved by the State Food and Drug Administration, are composed of Coptidis Rhizoma, Astragali Radix, and Lonicerae Japonicae Flos, and have a significant effect on diabetes. Coptidis Rhizoma is monarch drug in the prescription. The aim of the present study was to investigate and compare the pharmacokinetics of multiple ingredients from JQJT tablets and Coptidis Rhizoma extract (CRE) following oral administration in rats. Five alkaloids: coptisine chloride, epiberberine chloride, berberine chloride, jatrorrhizine chloride, and palmatine chloride, were simultaneously determined in rat plasma using established and validated ultra-high performance liquid chromatography mass spectrometry (UPLC-MS/MS). Significant pharmacokinetic differences were observed for the five alkaloids after a single administration of CRE and JQJT tablets. Compared with CRE, the Cmax values of palmatine chloride and jatrorrhizine chloride were decreased significantly, the AUC0–t values of four alkaloids (all except jatrorrhizine chloride) were notably decreased, and the mean residence times of all five alkaloids were significantly decreased after administration of JQJT tablets. The results indicated that the absorption characteristics of the five alkaloids from Coptidis Rhizoma would be influenced by the compatibility of Astragali Radix or Lonicerae Japonicae Flos from JQJT tablets, such that absorption was inhibited and elimination was accelerated. In conclusion, the developed strategy was suitable for the comparison of five alkaloids from JinQi Jiangtang tablets and its monarch drug, which could be valuable for compatibility studies of traditional Chinese medicines.

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<![CDATA[Endolysosomal Cation Channels and Cancer—A Link with Great Potential]]> https://www.researchpad.co/product?articleinfo=5b4cd5af463d7e0fba429df8

The endolysosomal system (ES) consists of lysosomes; early, late, and recycling endosomes; and autophagosomes. It is a key regulator not only of macromolecule degradation and recycling, plasma membrane repair, homeostasis, and lipid storage, but also of antigen presentation, immune defense, cell motility, cell death signaling, tumor growth, and cancer progression. In addition, it plays a critical role in autophagy, and the autophagy-lysosome pathway is intimately associated with the hallmarks of cancer, such as escaping cell death pathways, evading immune surveillance, and deregulating metabolism. The function of endolysosomes is critically dependent on both soluble and endolysosomal membrane proteins such as ion channels and transporters. Cation channels found in the ES include members of the TRP (transient receptor potential) channel superfamily, namely TRPML channels (mucolipins) as well as two-pore channels (TPCs). In recent studies, these channels have been found to play crucial roles in endolysosomal trafficking, lysosomal exocytosis, and autophagy. Mutation or loss of these channel proteins can impact multiple endolysosomal trafficking pathways. A role for TPCs in cancer cell migration and metastasis, linked to distinct defects in endolysosomal trafficking such as integrin trafficking, has been recently established. In this review, we give an overview on the function of lysosomes in cancer with a particular focus on the roles which TPCs and TRPML channels play in the ES and how this can affect cancer cells.

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<![CDATA[Benralizumab in the treatment of severe asthma: design, development and potential place in therapy]]> https://www.researchpad.co/product?articleinfo=5bfb917fd5eed0c484af96f5

Asthma is a widespread and heterogeneous inflammatory disease of the airways, which is characterized by several different phenotypes and endotypes. In particular, eosinophilic airway inflammation is a common pathologic trait of both allergic and nonallergic asthma. The key cytokine responsible for maturation, activation, recruitment, and survival of eosinophils is interleukin (IL)-5, which is mainly produced by T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells. Therefore, for uncontrolled patients with severe eosinophilic asthma, who are not fully responsive to corticosteroids, IL-5 represents a very important molecular target for add-on biological therapies. Among these new treatments, anti-IL-5 monoclonal antibodies such as mepolizumab and reslizumab have been developed and clinically evaluated. Furthermore, benralizumab is currently the only available biologic drug that specifically binds to the IL-5 receptor, thus preventing the interaction with its ligand and the consequent pro-inflammatory effects. The effectiveness of benralizumab in improving severe eosinophilic asthma has been well-documented by many randomized controlled trials.

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