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1.
Molecules ; 27(3)2022 Jan 28.
Article in English | MEDLINE | ID: covidwho-1686898

ABSTRACT

Cancer is the second most fatal disease worldwide, with colon cancer being the third most prevalent and fatal form of cancer in several Western countries. The risk of acquisition of resistance to chemotherapy remains a significant hurdle in the management of various types of cancer, especially colon cancer. Therefore, it is essential to develop alternative treatment modalities. Naturally occurring alkaloids have been shown to regulate various mechanistic pathways linked to cell proliferation, cell cycle, and metastasis. This review aims to shed light on the potential of alkaloids as anti-colon-cancer chemotherapy agents that can modulate or arrest the cell cycle. Preclinical investigated alkaloids have shown anti-colon cancer activities and inhibition of cancer cell proliferation via cell cycle arrest at different stages, suggesting that alkaloids may have the potential to act as anticancer molecules.


Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Colonic Neoplasms/drug therapy , Alkaloids/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Proliferation/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Drug Discovery , Humans
2.
Life Sci ; 295: 120411, 2022 Apr 15.
Article in English | MEDLINE | ID: covidwho-1683412

ABSTRACT

AIMS: Virus-infected host cells switch their metabolism to a more glycolytic phenotype, required for new virion synthesis and packaging. Therefore, we investigated the effect and mechanistic action of glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) on virus multiplication in host cells following SARS-CoV-2 infection. MAIN METHODS: SARS-CoV-2 induced change in glycolysis was examined in Vero E6 cells. Effect of 2-DG on virus multiplication was evaluated by RT-PCR (N and RdRp genes) analysis, protein expression analysis of Nucleocapsid (N) and Spike (S) proteins and visual indication of cytopathy effect (CPE), The mass spectrometry analysis was performed to examine the 2-DG induced change in glycosylation status of receptor binding domain (RBD) in SARS-CoV-2 spike protein. KEY FINDINGS: We observed SARS-COV-2 infection induced increased glucose influx and glycolysis, resulting in selectively high accumulation of the fluorescent glucose analog, 2-NBDG in Vero E6 cells. 2-DG inhibited glycolysis, reduced virus multiplication and alleviated cells from virus-induced cytopathic effect (CPE) in SARS-CoV-2 infected cells. The progeny virions produced from 2-DG treated cells were found unglycosylated at crucial N-glycosites (N331 and N343) of the receptor-binding domain (RBD) in the spike protein, resulting in production of defective progeny virions with compromised infective potential. SIGNIFICANCE: The mechanistic study revealed that the inhibition of SARS-COV-2 multiplication is attributed to 2-DG induced glycolysis inhibition and possibly un-glycosylation of the spike protein, also. Therefore, based on its previous human trials in different types of Cancer and Herpes patients, it could be a potential molecule to study in COVID-19 patients.


Subject(s)
COVID-19/drug therapy , Deoxyglucose/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Adenosine Triphosphate/metabolism , Animals , Antiviral Agents/pharmacology , COVID-19/metabolism , COVID-19/virology , Cell Proliferation/drug effects , Cell Survival/drug effects , Chlorocebus aethiops , Glucose/metabolism , Glycolysis/drug effects , Glycosylation , Host-Pathogen Interactions/drug effects , Mannose/pharmacology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virion/drug effects , Virion/pathogenicity , Virus Replication/drug effects
3.
Biosci Rep ; 41(12)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1592575

ABSTRACT

Parasporin-2Aa1 (PS2Aa1) is a toxic protein of 37 KDa (30 kDa, activated form produced by proteolysis) that was shown to be cytotoxic against specific human cancer cells, although its mechanism of action has not been elucidated yet. In order to study the role of some native peptide fragments of proteins on anticancer activity, here we investigated the cytotoxic effect of peptide fragments from domain-1 of PS2Aa1 and one of the loops present in the binding region of the virus spike protein from Alphacoronavirus (HCoV-229E), the latter according to scientific reports, who showed interaction with the human APN (h-APN) receptor, evidence corroborated through computational simulations, and thus being possible active against colon cancer cells. Peptides namely P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa were synthesized using the Fmoc solid-phase synthesis and characterized by mass spectrometry (MS). Additionally, one region from loop 1 of HCoV-229E, Loop1-HCoV-229E, was also synthesized and characterized. The A4W-GGN5 anticancer peptide and 5-fluorouracil (5-FU) were taken as a control in all experiments. Circular dichroism revealed an α-helix structure for the peptides derived from PS2Aa1 (P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa) and ß-laminar structure for the peptide derived from Alphacoronavirus spike protein Loop1-HCoV-229E. Peptides showed a hemolysis percentage of less than 20% at 100 µM concentration. Besides, peptides exhibited stronger anticancer activity against SW480 and SW620 cells after exposure for 48 h. Likewise, these compounds showed significantly lower toxicity against normal cells CHO-K1. The results suggest that native peptide fragments from Ps2Aa1 may be optimized as a novel potential cancer-therapeutic agents.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Endotoxins/pharmacology , Peptide Fragments/pharmacology , Spike Glycoprotein, Coronavirus/pharmacology , Alphacoronavirus , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , CD13 Antigens/metabolism , CHO Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cricetulus , Endotoxins/toxicity , Hemolysis/drug effects , Humans , Molecular Docking Simulation , Peptide Fragments/chemical synthesis , Peptide Fragments/toxicity , Protein Conformation, alpha-Helical , Sheep, Domestic , Spike Glycoprotein, Coronavirus/toxicity , Structure-Activity Relationship
4.
J Cell Mol Med ; 26(1): 235-238, 2022 01.
Article in English | MEDLINE | ID: covidwho-1555067

ABSTRACT

Due to the restrictions in accessing research laboratories and the challenges in providing proper storage and transportation of cells during the COVID-19 pandemic, having an effective and feasible mean to solve these challenges would be of immense help. Therefore, we developed a 3D culture setting of cancer cells using alginate beads and tested its effectiveness in different storage and transportation conditions. The viability and proliferation of cancer cells were assessed using trypan blue staining and quantitative CCK-8 kit, respectively. The developed beads allowed cancer cells survival up to 4 weeks with less frequent maintenance measures such as change of the culture media or subculture of cells. In addition, the recovery of cancer cells and proliferation pattern were significantly faster with better outcomes in the developed 3D alginate beads compared to the standard cryopreservation of cells or the 2D culture conditions. The 3D alginate beads also supported the viability of cells while the shipment at room temperature for a duration of up to 5 days with no humidity or CO2  support. Therefore, 3D culture in alginate beads can be used to store or ship biological cells with ease at room temperature with minimal preparations.


Subject(s)
Alginates/pharmacology , COVID-19/epidemiology , Cell Culture Techniques , Hydrogels/pharmacology , Osteoblasts/drug effects , A549 Cells , Alginates/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Hep G2 Cells , Humans , Hydrogels/chemistry , Osteoblasts/cytology , SARS-CoV-2/pathogenicity , Time Factors
5.
Viruses ; 13(12)2021 12 04.
Article in English | MEDLINE | ID: covidwho-1554971

ABSTRACT

Epidemic RNA viruses seem to arise year after year leading to countless infections and devastating disease. SARS-CoV-2 is the most recent of these viruses, but there will undoubtedly be more to come. While effective SARS-CoV-2 vaccines are being deployed, one approach that is still missing is effective antivirals that can be used at the onset of infections and therefore prevent pandemics. Here, we screened FDA-approved compounds against SARS-CoV-2. We found that atovaquone, a pyrimidine biosynthesis inhibitor, is able to reduce SARS-CoV-2 infection in human lung cells. In addition, we found that berberine chloride, a plant-based compound used in holistic medicine, was able to inhibit SARS-CoV-2 infection in cells through direct interaction with the virion. Taken together, these studies highlight potential avenues of antiviral development to block emerging viruses. Such proactive approaches, conducted well before the next pandemic, will be essential to have drugs ready for when the next emerging virus hits.


Subject(s)
Antiviral Agents/pharmacology , Atovaquone/pharmacology , Berberine/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Alveolar Epithelial Cells , Animals , Berberine/chemistry , Cell Proliferation/drug effects , Chlorides/chemistry , Chlorides/pharmacology , Chlorocebus aethiops , Drug Synergism , Humans , Proguanil/pharmacology , Vero Cells , Virion/drug effects
6.
Biosci Rep ; 41(12)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1526113

ABSTRACT

Parasporin-2Aa1 (PS2Aa1) is a toxic protein of 37 KDa (30 kDa, activated form produced by proteolysis) that was shown to be cytotoxic against specific human cancer cells, although its mechanism of action has not been elucidated yet. In order to study the role of some native peptide fragments of proteins on anticancer activity, here we investigated the cytotoxic effect of peptide fragments from domain-1 of PS2Aa1 and one of the loops present in the binding region of the virus spike protein from Alphacoronavirus (HCoV-229E), the latter according to scientific reports, who showed interaction with the human APN (h-APN) receptor, evidence corroborated through computational simulations, and thus being possible active against colon cancer cells. Peptides namely P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa were synthesized using the Fmoc solid-phase synthesis and characterized by mass spectrometry (MS). Additionally, one region from loop 1 of HCoV-229E, Loop1-HCoV-229E, was also synthesized and characterized. The A4W-GGN5 anticancer peptide and 5-fluorouracil (5-FU) were taken as a control in all experiments. Circular dichroism revealed an α-helix structure for the peptides derived from PS2Aa1 (P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa) and ß-laminar structure for the peptide derived from Alphacoronavirus spike protein Loop1-HCoV-229E. Peptides showed a hemolysis percentage of less than 20% at 100 µM concentration. Besides, peptides exhibited stronger anticancer activity against SW480 and SW620 cells after exposure for 48 h. Likewise, these compounds showed significantly lower toxicity against normal cells CHO-K1. The results suggest that native peptide fragments from Ps2Aa1 may be optimized as a novel potential cancer-therapeutic agents.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Endotoxins/pharmacology , Peptide Fragments/pharmacology , Spike Glycoprotein, Coronavirus/pharmacology , Alphacoronavirus , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , CD13 Antigens/metabolism , CHO Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cricetulus , Endotoxins/toxicity , Hemolysis/drug effects , Humans , Molecular Docking Simulation , Peptide Fragments/chemical synthesis , Peptide Fragments/toxicity , Protein Conformation, alpha-Helical , Sheep, Domestic , Spike Glycoprotein, Coronavirus/toxicity , Structure-Activity Relationship
7.
Theranostics ; 11(14): 7005-7017, 2021.
Article in English | MEDLINE | ID: covidwho-1524524

ABSTRACT

The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. Method: To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). Results: This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C in vitro and in vivo while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. In vivo pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. Conclusions: These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Indoles/pharmacology , Lung Neoplasms/drug therapy , Nanoparticles/chemistry , Phenothiazines/pharmacology , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/therapeutic use , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Nanoparticles/toxicity , Nanoparticles/ultrastructure , Phenothiazines/chemistry , Phenothiazines/pharmacokinetics , Phenothiazines/therapeutic use , Spectroscopy, Fourier Transform Infrared , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
8.
Clin Immunol ; 233: 108888, 2021 12.
Article in English | MEDLINE | ID: covidwho-1517099

ABSTRACT

Human interferon alpha (hIFN-α) administration constitutes the current FDA approved therapy for chronic Hepatitis B and C virus infections. Additionally, hIFN-α treatment efficacy was recently demonstrated in patients with COVID-19. Thus, hIFN-α constitutes a therapeutic alternative for those countries where vaccination is inaccessible and for people who did not respond effectively to vaccination. However, hIFN-α2b exhibits a short plasma half-life resulting in the occurrence of severe side effects. To optimize the cytokine's pharmacokinetic profile, we developed a hyperglycosylated IFN, referred to as GMOP-IFN. Given the significant number of reports showing neutralizing antibodies (NAb) formation after hIFN-α administration, here we applied the DeFT (De-immunization of Functional Therapeutics) approach to develop functional, de-immunized versions of GMOP-IFN. Two GMOP-IFN variants exhibited significantly reduced ex vivo immunogenicity and null antiproliferative activity, while preserving antiviral function. The results obtained in this work indicate that the new de-immunized GMOP-IFN variants constitute promising candidates for antiviral therapy.


Subject(s)
Hepatitis B, Chronic/immunology , Hepatitis C, Chronic/immunology , Interferon-alpha/immunology , Recombinant Proteins/immunology , Adult , Amino Acid Sequence , Animals , Antibodies, Neutralizing/immunology , Antiviral Agents/immunology , Antiviral Agents/pharmacology , CHO Cells , COVID-19/drug therapy , COVID-19/immunology , COVID-19/virology , Cattle , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cells, Cultured , Cricetinae , Cricetulus , Drug Stability , HEK293 Cells , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/virology , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Humans , Interferon-alpha/genetics , Interferon-alpha/pharmacology , Recombinant Proteins/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/physiology
9.
Molecules ; 26(21)2021 Oct 27.
Article in English | MEDLINE | ID: covidwho-1512508

ABSTRACT

As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide-alkyne cycloaddition, leading to the formation of the 1H-1,2,3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range), while the most selective harmirins were 5b and 12b, substituted at C-3 and O-7 of the ß-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs > 7.2). Further experiments demonstrated that harmirin 12b is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin 12b is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Coumarins/chemistry , Harmine/chemical synthesis , Harmine/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Harmine/analogs & derivatives , Humans , Molecular Structure
10.
Biomed Res Int ; 2021: 2610122, 2021.
Article in English | MEDLINE | ID: covidwho-1484095

ABSTRACT

OBJECTIVES: In this study, the cytotoxic responses of six different over-the-counter mouthwashes on L929 cells were analyzed by two different techniques: the traditional colorimetric tetrazolium-based reduction assay (MTT) and the modern impedance-based real-time cell analysis (RTCA) system to investigate their biocompatibility in vitro. Thus, the investigation of the antiproliferative effects of the specified materials via different techniques is vital to reach this goal. MATERIALS AND METHODS: First, L929 mouse fibroblasts were exposed to the dilutions of mouthwashes for 2 minutes. After incubation, the tetrazolium reduction method was used to assess the metabolic viability of cells measured by colorimetric MTT assay and morphological inspection of cells was performed via phase-contrast microscopy. Furthermore, the effect of each mouthwash on the proliferation, morphology, and adhesion of L929 cells was monitored continuously by a noninvasive and label-free RTCA system for 140 h. RESULTS: Our data showed that all of the mouthwashes had varying cytotoxic effects on fibroblasts compared to the control group in MTT assay. In addition to that, RTCA technology has provided the growth kinetic profiles that can be used to analyze if the treatment is causing antimitotic or DNA-damaging effect on cells. Thus, analysis via this system can tell us the mechanism of toxicity behind the cell growth inhibition in vitro. Here, we found that only mouthwash 1 moderately maintained the viability of the L929 cells, yet displaying antimitotic effects and the other mouthwashes (mouthwash 2-mouthwash 6) showed toxicity via DNA-damaging effects. CONCLUSIONS: Of the six types of mouthwash tested, the most biocompatible result was obtained from a mouthwash containing alcohol (i.e., mouthwash 1). On the other hand, sodium fluoride- (NaF-) and cetylpyridinium chloride- (CPC-) containing mouthwash (i.e., mouthwash 2) showed the most cytotoxic effect.


Subject(s)
Cetylpyridinium/pharmacology , Chlorhexidine/pharmacology , Ethanol/pharmacology , Mouthwashes/pharmacology , Sodium Fluoride/pharmacology , Animals , Anti-Infective Agents, Local/pharmacology , Cariostatic Agents/pharmacology , Cell Line , Cell Proliferation/drug effects , Mice , Mouthwashes/chemistry
11.
Int J Mol Sci ; 22(12)2021 Jun 20.
Article in English | MEDLINE | ID: covidwho-1472414

ABSTRACT

Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.


Subject(s)
Biological Therapy , Extracellular Vesicles/metabolism , Extracellular Vesicles/transplantation , Kidney Diseases/therapy , Mesenchymal Stem Cells/metabolism , Acute Kidney Injury/diagnosis , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Acute Kidney Injury/therapy , Animals , Apoptosis/drug effects , Biological Therapy/methods , Cell Differentiation , Cell Proliferation/drug effects , Cell Self Renewal , Chemical Fractionation , Disease Management , Disease Susceptibility , Exosomes/metabolism , Humans , Kidney Diseases/etiology , Kidney Diseases/pathology , Mesenchymal Stem Cells/cytology , Protective Agents , Renal Insufficiency/diagnosis , Renal Insufficiency/etiology , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/therapy
12.
Int J Mol Sci ; 22(19)2021 Oct 02.
Article in English | MEDLINE | ID: covidwho-1463709

ABSTRACT

Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18-1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4',6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biological Products/pharmacology , Triterpenes/pharmacology , Angiogenesis Inhibitors , Antineoplastic Agents/chemistry , Binding Sites , Biological Products/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Triterpenes/chemistry
13.
Adv Mater ; 33(52): e2105361, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1453531

ABSTRACT

Solid-state optics has been the pillar of modern digital age. Integrating soft hydrogel materials with micro/nanooptics could expand the horizons of photonics for bioengineering. Here, wet-spun multilayer hydrogel fibers are engineered through ionic-crosslinked natural polysaccharides that serve as multifunctional platforms. The resulting flexible hydrogel structure and reversible crosslinking provide tunable design properties such as adjustable refractive index and fusion splicing. Modulation of the optical readout via physical stimuli, including shape, compression, and multiple optical inputs/outputs is demonstrated. The unique permeability of the hydrogels is also combined with plasmonic nanoparticles for molecular detection of SARS-CoV-2 in fiber-coupled biomedical swabs. A tricoaxial 3D printing nozzle is then employed for the continuous fabrication of living optical fibers. Light interaction with living cells enables the quantification and digitalization of complex biological phenomena such as 3D cancer progression and drug susceptibility. These fibers pave the way for advances in biomaterial-based photonics and biosensing platforms.


Subject(s)
Hydrogels/chemistry , Optical Fibers , Optics and Photonics/methods , Polysaccharides/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biocompatible Materials/chemistry , Biosensing Techniques , COVID-19/diagnosis , COVID-19/virology , Cell Line, Tumor , Cell Proliferation/drug effects , Gold/chemistry , Humans , Metal Nanoparticles/chemistry , Neoplasms/drug therapy , Neoplasms/pathology , Printing, Three-Dimensional , SARS-CoV-2/isolation & purification
14.
Cells ; 10(9)2021 09 04.
Article in English | MEDLINE | ID: covidwho-1403545

ABSTRACT

Stroke is the third leading cause of mortality in women and it kills twice as many women as breast cancer. A key role in the pathophysiology of stroke plays the disruption of the blood-brain barrier (BBB) within the neurovascular unit. While estrogen induces vascular protective actions, its influence on stroke remains unclear. Moreover, experiments assessing its impact on endothelial cells to induce barrier integrity are non-conclusive. Since pericytes play an active role in regulating BBB integrity and function, we hypothesize that estradiol may influence BBB by regulating their activity. In this study using human brain vascular pericytes (HBVPs) we investigated the impact of estradiol on key pericyte functions known to influence BBB integrity. HBVPs expressed estrogen receptors (ER-α, ER-ß and GPER) and treatment with estradiol (10 nM) inhibited basal cell migration but not proliferation. Since pericyte migration is a hallmark for BBB disruption following injury, infection and inflammation, we investigated the effects of estradiol on TNFα-induced PC migration. Importantly, estradiol prevented TNFα-induced pericyte migration and this effect was mimicked by PPT (ER-α agonist) and DPN (ER-ß agonist), but not by G1 (GPR30 agonist). The modulatory effects of estradiol were abrogated by MPP and PHTPP, selective ER-α and ER-ß antagonists, respectively, confirming the role of ER-α and ER-ß in mediating the anti-migratory actions of estrogen. To delineate the intracellular mechanisms mediating the inhibitory actions of estradiol on PC migration, we investigated the role of AKT and MAPK activation. While estradiol consistently reduced the TNFα-induced MAPK and Akt phosphorylation, only the inhibition of MAPK, but not Akt, significantly abrogated the migratory actions of TNFα. In transendothelial electrical resistance measurements, estradiol induced barrier function (TEER) in human brain microvascular endothelial cells co-cultured with pericytes, but not in HBMECs cultured alone. Importantly, transcriptomics analysis of genes modulated by estradiol in pericytes showed downregulation of genes known to increase cell migration and upregulation of genes known to inhibit cell migration. Taken together, our findings provide the first evidence that estradiol modulates pericyte activity and thereby improves endothelial integrity.


Subject(s)
Brain/blood supply , Cell Movement/drug effects , Estradiol/pharmacology , Gene Expression Profiling , Pericytes/cytology , Cell Movement/genetics , Cell Proliferation/drug effects , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Gene Expression Regulation/drug effects , Humans , Mitogen-Activated Protein Kinases/metabolism , Pericytes/drug effects , Pericytes/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Estrogen/metabolism , Tumor Necrosis Factor-alpha/metabolism
15.
Bioorg Chem ; 116: 105346, 2021 11.
Article in English | MEDLINE | ID: covidwho-1401246

ABSTRACT

Starting from the antimalarial drugs chloroquine and hydroxychloroquine, we conducted a structural optimization on the side chain of chloroquine by introducing amino substituted longer chains thus leading to a series of novel aminochloroquine derivatives. Anti-infectious effects against SARS-Cov2 spike glycoprotein as well as immunosuppressive and anti-inflammatory activities of the new compounds were evaluated. Distinguished immunosuppressive activities on the responses of T cell, B cell and macrophages upon mitogen and pathogenic signaling were manifested. Compounds 9-11 displayed the most promising inhibitory effects both on cellular proliferation and on the production of multiple pro-inflammatory cytokines, including IL-17, IFN-γ, IL-6, IL-1ß and TNF-α, which might be insightful in the pursuit of treatment for immune disorders and inflammatory diseases.


Subject(s)
Amines/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , Chloroquine/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Amines/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , B-Lymphocytes/immunology , Cell Proliferation/drug effects , Chloroquine/chemical synthesis , Chloroquine/chemistry , Cytokines/metabolism , Dose-Response Relationship, Drug , Humans , Macrophages/drug effects , Macrophages/immunology , Microbial Sensitivity Tests , Molecular Structure , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
16.
Cancer Genomics Proteomics ; 18(5): 661-673, 2021.
Article in English | MEDLINE | ID: covidwho-1395533

ABSTRACT

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) poses a great challenge for the treatment of cancer patients. It presents as a severe respiratory infection in aged individuals, including some lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. In addition, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence, can worsen COVID-19. Given this situation, we investigated the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant non-small-cell lung cancer (NSCLC) cells (PC9-MET) to clarify the underlying mechanisms. MATERIALS AND METHODS: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, a reactive oxygen species (ROS) assay, SA-ß-Gal staining, a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Western blotting. RESULTS: Paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3 (Asp 175), cleaved caspase-9 (Asp 330) and cleaved PARP (Asp 214). In addition, paclitaxel increased ROS production, leading to DNA damage. Inhibition of ROS production by N-acetylcysteine attenuates paclitaxel-induced DNA damage. Importantly, paclitaxel eliminated cellular senescence, as observed by SA-ß-Gal staining. Cellular senescence elimination was associated with p53/p21 and p16/pRb signaling inactivation. CONCLUSION: Paclitaxel may be a promising anticancer drug and offer a new therapeutic strategy for managing gefitinib-resistant NSCLC during the COVID-19 pandemic.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/drug effects , Gefitinib/pharmacology , Lung Neoplasms/drug therapy , Paclitaxel/pharmacology , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cellular Senescence/drug effects , Humans , Lung Neoplasms/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects
17.
Cells ; 10(9)2021 08 31.
Article in English | MEDLINE | ID: covidwho-1390542

ABSTRACT

The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes ß-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived ß-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing ß-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small-molecule-induced human ß-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.


Subject(s)
Homeostasis , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/enzymology , Insulin/metabolism , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Genes, Reporter , Harmine/pharmacology , Homeostasis/drug effects , Humans , Induced Pluripotent Stem Cells/drug effects , Induced Pluripotent Stem Cells/metabolism , Insulin-Secreting Cells/drug effects , Kinetics , Male , Mice , Models, Biological , NFATC Transcription Factors/metabolism , Organoids/drug effects , Organoids/metabolism , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/metabolism , Rats , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/metabolism
18.
Biomed Pharmacother ; 140: 111596, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1385083

ABSTRACT

Flavonoids are natural phytochemicals known for their antiviral activity. The flavonoids acts at different stages of viral infection, such as viral entrance, replication and translation of proteins. Viruses cause various diseases such as SARS, Hepatitis, AIDS, Flu, Herpes, etc. These, and many more viral diseases, are prevalent in the world, and some (i.e. SARS-CoV-2) are causing global chaos. Despite much struggle, effective treatments for these viral diseases are not available. The flavonoid class of phytochemicals has a vast number of medicinally active compounds, many of which are studied for their potential antiviral activity against different DNA and RNA viruses. Here, we reviewed many flavonoids that showed antiviral activities in different testing environments such as in vitro, in vivo (mice model) and in silico. Some flavonoids had stronger inhibitory activities, showed no toxicity & the cell proliferation at the tested doses are not affected. Some of the flavonoids used in the in vivo studies also protected the tested mice prophylactically from lethal doses of virus, and effectively prevented viral infection. The glycosides of some of the flavonoids increased the solubility of some flavonoids, and therefore showed increased antiviral activity as compared to the non-glycoside form of that flavonoid. These phytochemicals are active against different disease-causing viruses, and inhibited the viruses by targeting the viral infections at multiple stages. Some of the flavonoids showed more potent antiviral activity than the market available drugs used to treat viral infections.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Flavonoids/pharmacology , Flavonoids/therapeutic use , Virus Diseases/drug therapy , Viruses/drug effects , Animals , Cell Proliferation/drug effects , Glycosides/metabolism , Humans , Virus Diseases/metabolism
19.
Int J Mol Sci ; 22(15)2021 Jul 27.
Article in English | MEDLINE | ID: covidwho-1332900

ABSTRACT

A novel series of N-substituted cis- and trans-3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl-(diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3-H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC50 = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC50 = 12 µM by visual CPE score; EC50 = 8.3 µM by TMS score; MCC > 100 µM, CC50 = 39.9 µM). Several azetidin-2-ones 10 and 11 were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC50 in the range 14.5-97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S. aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at ß-lactamase, thus protecting the antibiotic from undesirable biotransformation.


Subject(s)
Adjuvants, Pharmaceutic/chemistry , Adjuvants, Pharmaceutic/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Azetidines/pharmacology , Infections/drug therapy , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Azetidines/chemistry , Bacterial Proteins/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Coronavirus 229E, Human/drug effects , Cytostatic Agents/chemistry , Cytostatic Agents/pharmacology , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Molecular Dynamics Simulation , Oxacillin/chemistry , Penicillin-Binding Proteins/chemistry , Staphylococcus aureus/drug effects , Stereoisomerism , beta-Lactamases/chemistry
20.
Pharmacol Res ; 158: 104850, 2020 08.
Article in English | MEDLINE | ID: covidwho-1318927

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread worldwide through person-to-person contact, causing a public health emergency of international concern. At present, there is no specific antiviral treatment recommended for SARS-CoV-2 infection. Liu Shen capsule (LS), a traditional Chinese medicine, has been proven to have a wide spectrum of pharmacological properties, such as anti-inflammatory, antiviral and immunomodulatory activities. However, little is known about the antiviral effect of LS against SARS-CoV-2. Herein, the study was designed to investigate the antiviral activity of SARS-CoV-2 and its potential effect in regulating the host's immune response. The inhibitory effect of LS against SARS-CoV-2 replication in Vero E6 cells was evaluated by using the cytopathic effect (CPE) and plaque reduction assay. The number of virions of SARS-CoV-2 was observed under transmission electron microscope after treatment with LS. Proinflammatory cytokine expression levels upon SARS-CoV-2 infection in Huh-7 cells were measured by real-time quantitative PCR assays. The results showed that LS could significantly inhibit SARS-CoV-2 replication in Vero E6 cells, and reduce the number of virus particles and it could markedly reduce pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß, IL-8, CCL-2/MCP-1 and CXCL-10/IP-10) production at the mRNA levels. Moreover, the expression of the key proteins in the NF-κB/MAPK signaling pathway was detected by western blot and it was found that LS could inhibit the expression of p-NF-κB p65, p-IκBα and p-p38 MAPK, while increasing the expression of IκBα. These findings indicate that LS could inhibit SARS-CoV-2 virus infection via downregulating the expression of inflammatory cytokines induced virus and regulating the activity of NF-κB/MAPK signaling pathway in vitro, making its promising candidate treatment for controlling COVID-19 disease.


Subject(s)
Betacoronavirus/drug effects , Complex Mixtures/pharmacology , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Signal Transduction/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19 , Cell Proliferation/drug effects , Cells, Cultured , Chlorocebus aethiops , Coronavirus Infections/virology , Humans , Inflammation Mediators/metabolism , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Virion/drug effects
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