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Détails du magazine
Format
Magazine
eISSN
1846-9558
Première publication
28 Feb 2007
Période de publication
4 fois par an
Langues
Anglais

Chercher

Volume 71 (2021): Edition 2 (June 2021)

Détails du magazine
Format
Magazine
eISSN
1846-9558
Première publication
28 Feb 2007
Période de publication
4 fois par an
Langues
Anglais

Chercher

10 Articles
Accès libre

Identification of potential COVID-19 main protease inhibitors using structure-based pharmacophore approach, molecular docking and repurposing studies

Publié en ligne: 04 Nov 2020
Pages: 163 - 174

Résumé

Abstract

The current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today’s diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.

Mots clés

  • COVID-19
  • main protease
  • pharmacophore
  • structure-based modeling
  • docking study
  • remdesivir
  • repurposing
Accès libre

Sitagliptin: a potential drug for the treatment of COVID-19?

Publié en ligne: 04 Nov 2020
Pages: 175 - 184

Résumé

Abstract

Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality.

Mots clés

  • SARS-CoV-2
  • COVID-19
  • DPP4
  • ACE2
  • sitagliptin
  • drug repurposing
  • CXCL10
Accès libre

Piperine: Chemical, biological and nanotechnological applications

Publié en ligne: 04 Nov 2020
Pages: 185 - 213

Résumé

Abstract

Piperine (PIP) is an alkaloid present in several species of piper, mainly Piper nigrum Linn. and P. longum, among other species. The present article provides a comprehensive review of PIP research in the last years concerning its chemical properties, synthesis, absorption, metabolism, bioavailability and toxicity. The reviewed PIP literature has shown many pharmacological properties, such as antidiabetic, antidiarrheal, antioxidant, antibacterial, and anti-parasitic activity of PIP. However, its low solubility and absorption make its application challenging. This review also includes advances in the development of nanosystems containing PIP, including liposomes, micelles, metal nanoparticles, nanofibers, polymeric nanoparticles, and solid-lipid nanoparticles. Finally, we discuss different in vitro and in vivo studies to evaluate the biological activity of this drug, as well as some methods for the synthesis of nanosystems and their physical characteristics.

Mots clés

  • absorption
  • metabolism
  • pharmacological activity
  • nanosystems
Accès libre

Polyethylene oxide matrix tablet swelling evolution: The impact of molecular mass and tablet composition

Publié en ligne: 04 Nov 2020
Pages: 215 - 243

Résumé

Abstract

This article describes the designing of matrix tablets composed of polyethylene oxides (PEOs) with relative molecular masses of 1 × 106, 2 × 106, and 4 × 106. Percolation thresholds were determined for all of the selected PEO formulations (18, 16, and 12 %, m/m), taking into consideration excipients and tablet surface area which significantly increased the percolation threshold. Moreover, the robustness of the gel layer in PEO matrix tablets was evaluated by magnetic resonance imaging under various mechanical stresses (no flow, 12 mL min−1, and 64 mL−1 of medium flow). Correlations between the percolation threshold and gel thickness (R2 = 0.86), gel thickness and the erosion coefficient (R2 = 0.96) was detected. Furthermore, small-angle X-ray scattering of the selected PEOs detected differences in polymer molecular complexity at the nanoscale. Finally, the ratio of the heat of coalescence to the heat of fusion has confirmed the PEO molecular mass-dependent percolation threshold.

Mots clés

  • polyethylene oxide
  • MRI
  • percolation threshold
  • SAXS
  • WAXS
Accès libre

Tryptanthrin exerts anti-breast cancer effects both in vitro and in vivo through modulating the inflammatory tumor microenvironment

Publié en ligne: 04 Nov 2020
Pages: 245 - 266

Résumé

Abstract

Tryptanthrin is an indole quinazoline alkaloid from the indigo-bearing plants, such as Isatis indigotica Fort. Typically, this natural compound shows a variety of pharmacological activities such as antitumor, antibacterial, anti-inflammatory and antioxidant effects. This study was conducted to assess the antitumor activity of tryptanthrin in breast cancer models both in vitro and in vivo, and to explore the important role of the inflammatory tumor microenvironment (TME) in the antitumor effects of tryptanthrin. Human breast adenocarcinoma MCF-7 cells were used to assess the antitumor effect of tryptanthrin in vitro. MTT assay and colony formation assay were carried out to monitor the antiproliferative effect of tryptanthrin (1.56~50.0 μmol L−1) on inhibiting the proliferation and colony formation of MCF-7 cells, respectively. The migration and invasion of MCF-7 cells were evaluated by wound healing assay and Transwell chamber assay, respectively. Moreover, the 4T1 murine breast cancer model was established to examine the pharmacological activity of tryptanthrin, and three groups with different doses of tryptanthrin (25, 50 and 100 mg kg−1) were set in study. Additionally, tumor volumes and organ coefficients were measured and calculated. After two weeks of tryptanthrin treatment, samples from serum, tumor tissue and different organs from tumor-bearing mice were collected, and the enzyme-linked immunosorbent assay (ELISA) was performed to assess the regulation of inflammatory molecules in mouse serum. Additionally, pathological examinations of tumor tissues and organs from mice were evaluated through hematoxylin and eosin (H&E) staining. The expression of inflammatory proteins in tumor tissues was measured by immunohistochemistry (IHC) and Western blotting. Tryptanthrin inhibited the proliferation, migration and invasion of MCF-7 cells, up-regulated the protein level of E-cadherin, and down-regulated those of MMP-2 and Snail, as suggested by the MCF-7 cell experiment. According to the results from in vivo experiment, tryptanthrin was effective in inhibiting tumor growth, and it showed favorable safety without inducing the fluctuations of body mass and organ coefficient (p > 0.05). In addition, tryptanthrin also suppressed the expression levels of NOS1, COX-2 and NF-κB in mouse tumor tissues, and regulated those of IL-2, IL-10 and TNF-α in the serum of tumor cells-transplanted mice. Tryptanthrin exerted its anti-breast cancer activities through modulating the inflammatory TME both in vitro and in vivo.

Mots clés

  • tryptanthrin
  • antitumor
  • inflammatory tumor microenvironment
  • epithelial-mesenchymal transition
  • natural medicine
Accès libre

Norcantharidin induces G2/M arrest and apoptosis via activation of ERK and JNK, but not p38 signaling in human renal cell carcinoma ACHN cells

Publié en ligne: 04 Nov 2020
Pages: 267 - 278

Résumé

Abstract

Renal cell carcinoma (RCC) is generally acknowledged as the most resistant primary malignancy unresponsive to conventional radiotherapy and chemotherapy treatments. Norcantharidin (NCTD), a therapeutic compound derived from medicinal plants, has been shown to trigger apoptosis, as well as antimetastatic and antioxidant activities in several tumor cells. However, NCTD’s mechanism of antitumor activity in the RCC cell line remains unclear. In this study, we report that NCTD led to a time- and dose-dependent inhibition of cell proliferation. It had also markedly induced apoptosis and G2/M phase cell cycle arrest in a dose-dependent manner by decreasing the expressions of pro-caspase-3, pro-caspase-9, cyclin B1, and pCDC25C while increasing active caspase-3, cleaved-PARP, P21, and pCDC2 levels. Interestingly, NCTD treatment provoked the phosphorylation of extracellular-regulated protein kinase (ERK) and c-Jun-N-terminal kinase (JNK), but not of p38 MAPK. Moreover, SCH772984 and SP600125, ERK and JNK inhibitors, respectively, could partially abolish NCTD-induced apoptosis and G2/M phase cell cycle arrest. Collectively, these findings suggest that NCTD might activate JNK and ERK signaling pathways, consequently inducing apoptosis and G2/M arrest through the modulation of related proteins. This study provided evidence that NCTD is a promising therapeutic drug for the treatment of RCC.

Mots clés

  • norcantharidin
  • renal cancer cells
  • ERK
  • JNK
  • p38 MAPK
  • apoptosis
  • cell cycle arrest
Accès libre

Efficacy and safety of the metformin-mazindol anorectic combination in rat

Publié en ligne: 04 Nov 2020
Pages: 279 - 291

Résumé

Abstract

The current study investigates the anorectic interaction and safety of the mazindol-metformin combination in rats. Isobologram and interaction index were used to determine anorectic interaction between mazindol and metformin in the sweetened milk model. The safety profile of the mazindol-metformin combination was determined by measuring anxiety, blood pressure, hematic biometry and blood chemistry. An acute dose of mazindol and metformin administered per os, individually or as a mixture, has reduced the milk consumption in rats in a dose-dependent manner. Theoretical effective dose 40 (ED40t) did not differ from the experimental effective dose 40 (ED40e) obtained with the mazindol-metformin mixture in the anorexia experiments, by Student′s t-test. In addition, the interaction index confirmed the additive anorectic effect between both drugs. A single oral dose of ED40e mazindol-metformin mixture induced anxiolysis in the elevated plus-maze test. Moreover, oral administration of mazindol-metformin combination for 3 months significantly decreased glycemia, but not blood pressure nor other parameters of hematic biometry and blood chemistry. Results suggest that mazindol-metformin combination exerts an additive anorectic effect, as well as anxiolytic and hypoglycemic properties. Mazindol-metformin combination might be useful in obese patients with anxiety disorders or diabetes risk factors.

Mots clés

  • mazindol-metformin combination
  • anorectic interaction
  • anxiolysis
  • hypoglycemic effect
Accès libre

Ultraviolet B irradiation-induced keratinocyte senescence and impaired development of 3D epidermal reconstruct

Publié en ligne: 04 Nov 2020
Pages: 293 - 303

Résumé

Abstract

Ultraviolet B (UVB) induces morphological and functional changes of the skin. This study investigated the effect of UVB on keratinocyte senescence and the development of reconstructed human epidermis (RHE). Primary normal human keratinocytes (NHK) from juvenile foreskin were irradiated with UVB (30 mJ cm−2) and these effects were compared to NHK that underwent senescence in the late passage. UVB enhanced the accumulation of reactive oxygen species (ROS) and halted cell replication as detected by BrdU cell proliferation assay. The senescence phenotype was evaluated by beta-galactosidase (β-gal) staining and qPCR of genes related to senescent regulation, i.e. p16INK4a, cyclin D2, and IFI27. Senescence induced by high dose UVB resulted in morphological changes, enhanced β-gal activity, elevated cellular ROS levels and reduced DNA synthesis. qPCR revealed differential expression of the genes regulated senescence. p16INK4a expression was significantly increased in NHK exposed to UVB whereas enhanced IFI27 expression was observed only in cultural senescence. The levels of cyclin D2 expression were not significantly altered either by UVB or long culturing conditions. UVB significantly induced the aging phenotype in keratinocytes and impaired epidermal development. RHE generated from UVB-irradiated keratinocytes showed a thinner cross-sectional structure and the majority of keratinocytes in the lower epidermis were degenerated. The 3D epidermis model is useful in studying the skin aging process.

Mots clés

  • epidermis
  • keratinocytes
  • ultraviolet radiation
  • skin aging
  • senescence
  • reactive oxygen species
Accès libre

A new RP-HPLC method as an auxiliary tool for optimization of sample preparation procedures for tracing of PPCPs of different hydrophilicities

Publié en ligne: 04 Nov 2020
Pages: 305 - 315

Résumé

Abstract

Recently, pharmaceutical and personal care products (PPCPs) have received considerable attention because of their increasing use. Analysis of PPCPs presents a significant analytical challenge, with high-performance liquid chromatography (HPLC) in reversed-phase mode, as the most widely used analytical technique. To facilitate the optimization of the procedures that are applied in the early stages of sample preparation, a simple and fast HPLC method is proposed in this work for the separation of some PPCPs with a wide range of hydrophilicity. Two columns were evaluated (Atlantis dC18 and Discovery HS F5); as for mobile phases: a formate buffer (40 mmol L−1, pH 4) and methanol were tested in a gradient mode. The fluorinated column allowed better separation in a shorter time and better resolution for all analytes (Rs > 1). The proposed method delivered good performance for the tracing of PPCPs and is a suitable alternative to traditional C18-based HPLC methods.

Mots clés

  • pharmaceutical and personal care products
  • reversed-phase high-performance liquid chromatography
  • ultraviolet detection
Accès libre

Inhibitory effect of terfenadine on Kir2.1 and Kir2.3 channels

Publié en ligne: 04 Nov 2020
Pages: 317 - 324

Résumé

Abstract

Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer properties. Lately, the subfamily 2 of inward rectifier potassium channels (Kir2) has been implicated in the progression of some tumoral processes. Hence, we characterized the effects of terfenadine on Kir2.x channels expressed in HEK-293 cells. Terfenadine inhibited Kir2.3 channels with a strikingly greater potency (IC50 = 1.06 ± 0.11 μmol L−1) compared to Kir2.1 channels (IC50 = 27.8 ± 4.8 μmol L−1). The Kir2.3(I213L) mutant, possessing a larger affinity for phosphatidylinositol 4,5-bisphosphate (PIP2) than the wild-type Kir2.3, was less sensitive to terfenadine inhibition (IC50 = 13.0 ± 2.9 μmol L−1). Additionally, the PIP2 intracellular application had largely reduced the inhibition of Kir2.1 channels by terfenadine. Our data support that Kir2.x channels are targets of terfena-dine by affecting their interaction with PIP2, which could be regarded as a mechanism of the antitumor properties of terfenadine.

Mots clés

  • terfenadine
  • inward rectifier potassium channels
  • phosphatidylinositol 4,5-bisphosphate
  • cationic amphiphilic drugs
10 Articles
Accès libre

Identification of potential COVID-19 main protease inhibitors using structure-based pharmacophore approach, molecular docking and repurposing studies

Publié en ligne: 04 Nov 2020
Pages: 163 - 174

Résumé

Abstract

The current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today’s diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.

Mots clés

  • COVID-19
  • main protease
  • pharmacophore
  • structure-based modeling
  • docking study
  • remdesivir
  • repurposing
Accès libre

Sitagliptin: a potential drug for the treatment of COVID-19?

Publié en ligne: 04 Nov 2020
Pages: 175 - 184

Résumé

Abstract

Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality.

Mots clés

  • SARS-CoV-2
  • COVID-19
  • DPP4
  • ACE2
  • sitagliptin
  • drug repurposing
  • CXCL10
Accès libre

Piperine: Chemical, biological and nanotechnological applications

Publié en ligne: 04 Nov 2020
Pages: 185 - 213

Résumé

Abstract

Piperine (PIP) is an alkaloid present in several species of piper, mainly Piper nigrum Linn. and P. longum, among other species. The present article provides a comprehensive review of PIP research in the last years concerning its chemical properties, synthesis, absorption, metabolism, bioavailability and toxicity. The reviewed PIP literature has shown many pharmacological properties, such as antidiabetic, antidiarrheal, antioxidant, antibacterial, and anti-parasitic activity of PIP. However, its low solubility and absorption make its application challenging. This review also includes advances in the development of nanosystems containing PIP, including liposomes, micelles, metal nanoparticles, nanofibers, polymeric nanoparticles, and solid-lipid nanoparticles. Finally, we discuss different in vitro and in vivo studies to evaluate the biological activity of this drug, as well as some methods for the synthesis of nanosystems and their physical characteristics.

Mots clés

  • absorption
  • metabolism
  • pharmacological activity
  • nanosystems
Accès libre

Polyethylene oxide matrix tablet swelling evolution: The impact of molecular mass and tablet composition

Publié en ligne: 04 Nov 2020
Pages: 215 - 243

Résumé

Abstract

This article describes the designing of matrix tablets composed of polyethylene oxides (PEOs) with relative molecular masses of 1 × 106, 2 × 106, and 4 × 106. Percolation thresholds were determined for all of the selected PEO formulations (18, 16, and 12 %, m/m), taking into consideration excipients and tablet surface area which significantly increased the percolation threshold. Moreover, the robustness of the gel layer in PEO matrix tablets was evaluated by magnetic resonance imaging under various mechanical stresses (no flow, 12 mL min−1, and 64 mL−1 of medium flow). Correlations between the percolation threshold and gel thickness (R2 = 0.86), gel thickness and the erosion coefficient (R2 = 0.96) was detected. Furthermore, small-angle X-ray scattering of the selected PEOs detected differences in polymer molecular complexity at the nanoscale. Finally, the ratio of the heat of coalescence to the heat of fusion has confirmed the PEO molecular mass-dependent percolation threshold.

Mots clés

  • polyethylene oxide
  • MRI
  • percolation threshold
  • SAXS
  • WAXS
Accès libre

Tryptanthrin exerts anti-breast cancer effects both in vitro and in vivo through modulating the inflammatory tumor microenvironment

Publié en ligne: 04 Nov 2020
Pages: 245 - 266

Résumé

Abstract

Tryptanthrin is an indole quinazoline alkaloid from the indigo-bearing plants, such as Isatis indigotica Fort. Typically, this natural compound shows a variety of pharmacological activities such as antitumor, antibacterial, anti-inflammatory and antioxidant effects. This study was conducted to assess the antitumor activity of tryptanthrin in breast cancer models both in vitro and in vivo, and to explore the important role of the inflammatory tumor microenvironment (TME) in the antitumor effects of tryptanthrin. Human breast adenocarcinoma MCF-7 cells were used to assess the antitumor effect of tryptanthrin in vitro. MTT assay and colony formation assay were carried out to monitor the antiproliferative effect of tryptanthrin (1.56~50.0 μmol L−1) on inhibiting the proliferation and colony formation of MCF-7 cells, respectively. The migration and invasion of MCF-7 cells were evaluated by wound healing assay and Transwell chamber assay, respectively. Moreover, the 4T1 murine breast cancer model was established to examine the pharmacological activity of tryptanthrin, and three groups with different doses of tryptanthrin (25, 50 and 100 mg kg−1) were set in study. Additionally, tumor volumes and organ coefficients were measured and calculated. After two weeks of tryptanthrin treatment, samples from serum, tumor tissue and different organs from tumor-bearing mice were collected, and the enzyme-linked immunosorbent assay (ELISA) was performed to assess the regulation of inflammatory molecules in mouse serum. Additionally, pathological examinations of tumor tissues and organs from mice were evaluated through hematoxylin and eosin (H&E) staining. The expression of inflammatory proteins in tumor tissues was measured by immunohistochemistry (IHC) and Western blotting. Tryptanthrin inhibited the proliferation, migration and invasion of MCF-7 cells, up-regulated the protein level of E-cadherin, and down-regulated those of MMP-2 and Snail, as suggested by the MCF-7 cell experiment. According to the results from in vivo experiment, tryptanthrin was effective in inhibiting tumor growth, and it showed favorable safety without inducing the fluctuations of body mass and organ coefficient (p > 0.05). In addition, tryptanthrin also suppressed the expression levels of NOS1, COX-2 and NF-κB in mouse tumor tissues, and regulated those of IL-2, IL-10 and TNF-α in the serum of tumor cells-transplanted mice. Tryptanthrin exerted its anti-breast cancer activities through modulating the inflammatory TME both in vitro and in vivo.

Mots clés

  • tryptanthrin
  • antitumor
  • inflammatory tumor microenvironment
  • epithelial-mesenchymal transition
  • natural medicine
Accès libre

Norcantharidin induces G2/M arrest and apoptosis via activation of ERK and JNK, but not p38 signaling in human renal cell carcinoma ACHN cells

Publié en ligne: 04 Nov 2020
Pages: 267 - 278

Résumé

Abstract

Renal cell carcinoma (RCC) is generally acknowledged as the most resistant primary malignancy unresponsive to conventional radiotherapy and chemotherapy treatments. Norcantharidin (NCTD), a therapeutic compound derived from medicinal plants, has been shown to trigger apoptosis, as well as antimetastatic and antioxidant activities in several tumor cells. However, NCTD’s mechanism of antitumor activity in the RCC cell line remains unclear. In this study, we report that NCTD led to a time- and dose-dependent inhibition of cell proliferation. It had also markedly induced apoptosis and G2/M phase cell cycle arrest in a dose-dependent manner by decreasing the expressions of pro-caspase-3, pro-caspase-9, cyclin B1, and pCDC25C while increasing active caspase-3, cleaved-PARP, P21, and pCDC2 levels. Interestingly, NCTD treatment provoked the phosphorylation of extracellular-regulated protein kinase (ERK) and c-Jun-N-terminal kinase (JNK), but not of p38 MAPK. Moreover, SCH772984 and SP600125, ERK and JNK inhibitors, respectively, could partially abolish NCTD-induced apoptosis and G2/M phase cell cycle arrest. Collectively, these findings suggest that NCTD might activate JNK and ERK signaling pathways, consequently inducing apoptosis and G2/M arrest through the modulation of related proteins. This study provided evidence that NCTD is a promising therapeutic drug for the treatment of RCC.

Mots clés

  • norcantharidin
  • renal cancer cells
  • ERK
  • JNK
  • p38 MAPK
  • apoptosis
  • cell cycle arrest
Accès libre

Efficacy and safety of the metformin-mazindol anorectic combination in rat

Publié en ligne: 04 Nov 2020
Pages: 279 - 291

Résumé

Abstract

The current study investigates the anorectic interaction and safety of the mazindol-metformin combination in rats. Isobologram and interaction index were used to determine anorectic interaction between mazindol and metformin in the sweetened milk model. The safety profile of the mazindol-metformin combination was determined by measuring anxiety, blood pressure, hematic biometry and blood chemistry. An acute dose of mazindol and metformin administered per os, individually or as a mixture, has reduced the milk consumption in rats in a dose-dependent manner. Theoretical effective dose 40 (ED40t) did not differ from the experimental effective dose 40 (ED40e) obtained with the mazindol-metformin mixture in the anorexia experiments, by Student′s t-test. In addition, the interaction index confirmed the additive anorectic effect between both drugs. A single oral dose of ED40e mazindol-metformin mixture induced anxiolysis in the elevated plus-maze test. Moreover, oral administration of mazindol-metformin combination for 3 months significantly decreased glycemia, but not blood pressure nor other parameters of hematic biometry and blood chemistry. Results suggest that mazindol-metformin combination exerts an additive anorectic effect, as well as anxiolytic and hypoglycemic properties. Mazindol-metformin combination might be useful in obese patients with anxiety disorders or diabetes risk factors.

Mots clés

  • mazindol-metformin combination
  • anorectic interaction
  • anxiolysis
  • hypoglycemic effect
Accès libre

Ultraviolet B irradiation-induced keratinocyte senescence and impaired development of 3D epidermal reconstruct

Publié en ligne: 04 Nov 2020
Pages: 293 - 303

Résumé

Abstract

Ultraviolet B (UVB) induces morphological and functional changes of the skin. This study investigated the effect of UVB on keratinocyte senescence and the development of reconstructed human epidermis (RHE). Primary normal human keratinocytes (NHK) from juvenile foreskin were irradiated with UVB (30 mJ cm−2) and these effects were compared to NHK that underwent senescence in the late passage. UVB enhanced the accumulation of reactive oxygen species (ROS) and halted cell replication as detected by BrdU cell proliferation assay. The senescence phenotype was evaluated by beta-galactosidase (β-gal) staining and qPCR of genes related to senescent regulation, i.e. p16INK4a, cyclin D2, and IFI27. Senescence induced by high dose UVB resulted in morphological changes, enhanced β-gal activity, elevated cellular ROS levels and reduced DNA synthesis. qPCR revealed differential expression of the genes regulated senescence. p16INK4a expression was significantly increased in NHK exposed to UVB whereas enhanced IFI27 expression was observed only in cultural senescence. The levels of cyclin D2 expression were not significantly altered either by UVB or long culturing conditions. UVB significantly induced the aging phenotype in keratinocytes and impaired epidermal development. RHE generated from UVB-irradiated keratinocytes showed a thinner cross-sectional structure and the majority of keratinocytes in the lower epidermis were degenerated. The 3D epidermis model is useful in studying the skin aging process.

Mots clés

  • epidermis
  • keratinocytes
  • ultraviolet radiation
  • skin aging
  • senescence
  • reactive oxygen species
Accès libre

A new RP-HPLC method as an auxiliary tool for optimization of sample preparation procedures for tracing of PPCPs of different hydrophilicities

Publié en ligne: 04 Nov 2020
Pages: 305 - 315

Résumé

Abstract

Recently, pharmaceutical and personal care products (PPCPs) have received considerable attention because of their increasing use. Analysis of PPCPs presents a significant analytical challenge, with high-performance liquid chromatography (HPLC) in reversed-phase mode, as the most widely used analytical technique. To facilitate the optimization of the procedures that are applied in the early stages of sample preparation, a simple and fast HPLC method is proposed in this work for the separation of some PPCPs with a wide range of hydrophilicity. Two columns were evaluated (Atlantis dC18 and Discovery HS F5); as for mobile phases: a formate buffer (40 mmol L−1, pH 4) and methanol were tested in a gradient mode. The fluorinated column allowed better separation in a shorter time and better resolution for all analytes (Rs > 1). The proposed method delivered good performance for the tracing of PPCPs and is a suitable alternative to traditional C18-based HPLC methods.

Mots clés

  • pharmaceutical and personal care products
  • reversed-phase high-performance liquid chromatography
  • ultraviolet detection
Accès libre

Inhibitory effect of terfenadine on Kir2.1 and Kir2.3 channels

Publié en ligne: 04 Nov 2020
Pages: 317 - 324

Résumé

Abstract

Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer properties. Lately, the subfamily 2 of inward rectifier potassium channels (Kir2) has been implicated in the progression of some tumoral processes. Hence, we characterized the effects of terfenadine on Kir2.x channels expressed in HEK-293 cells. Terfenadine inhibited Kir2.3 channels with a strikingly greater potency (IC50 = 1.06 ± 0.11 μmol L−1) compared to Kir2.1 channels (IC50 = 27.8 ± 4.8 μmol L−1). The Kir2.3(I213L) mutant, possessing a larger affinity for phosphatidylinositol 4,5-bisphosphate (PIP2) than the wild-type Kir2.3, was less sensitive to terfenadine inhibition (IC50 = 13.0 ± 2.9 μmol L−1). Additionally, the PIP2 intracellular application had largely reduced the inhibition of Kir2.1 channels by terfenadine. Our data support that Kir2.x channels are targets of terfena-dine by affecting their interaction with PIP2, which could be regarded as a mechanism of the antitumor properties of terfenadine.

Mots clés

  • terfenadine
  • inward rectifier potassium channels
  • phosphatidylinositol 4,5-bisphosphate
  • cationic amphiphilic drugs

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