C-C chemokine receptor type 5 links COVID-19, rheumatoid arthritis, and Hydroxychloroquine: in silico analysis

Abstract Patients with rheumatoid arthritis (RA) represent one of the fragile patient groups that might be susceptible to the critical form of the coronavirus disease − 19 (COVID-19). On the other side, RA patients have been found not to have an increased risk of COVID-19 infection. Moreover, some of the Disease-Modifying Anti-Rheumatic Drugs (DMARDS) commonly used to treat rheumatic diseases like Hydroxychloroquine (HCQ) were proposed as a potential therapy for COVID-19 with a lack of full understanding of their molecular mechanisms. This highlights the need for the discovery of common pathways that may link both diseases at the molecular side. In this research, we used the in silico approach to investigate the transcriptomic profile of RA synovium to identify shared molecular pathways with that of severe acute respiratory syndrome-corona virus-2 (SARS-COV-2) infected lung tissue. Our results showed upregulation of chemotactic factors, including CCL4, CCL8, and CCL11, that all shared CCR5 as their receptor, as a common derangement observed in both diseases; RA and COVID-19. Moreover, our results also highlighted a possible mechanism through which HCQ, which can be used as a monotherapy in mild RA or as one of the triple-DMARDs therapy (tDMARDs; methotrexate, sulphasalazine, and HCQ), might interfere with the COVID-19 infection. This might be achieved through the ability of HCQ to upregulate specific immune cell populations like activated natural killer (NK) cells, which were found to be significantly reduced in COVID-19 infection. In addition to its ability to block CCR5 rich immune cell recruitment that also was upregulated in the SARS-COV-2 infected lungs. This might explain some of the reports that showed beneficial effects.

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C-C chemokine receptor type 5 links COVID-19, Rheumatoid arthritis, and Hydroxychloroquine: In silico analysis

10.21203/rs.3.rs-48001/v2 ◽

2020 ◽

Author(s):

MAHMOOD Yaseen HACHIM ◽

Ibrahim Hachim ◽

Kashif Naeem ◽

Haifa Hannawi ◽

Issa Al Salmi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

In Silico ◽

Molecular Mechanisms ◽

Immune Cell ◽

In Silico Analysis ◽

Cell Recruitment ◽

Beneficial Effects ◽

Increased Risk ◽

Patient Groups ◽

Chemotactic Factors

Abstract Patients with rheumatoid arthritis (RA) represent one of the fragile patient groups that might be susceptible to the critical form of the coronavirus disease -19 (COVID-19) . On the other side, RA patients have been found not to have an increased risk of COVID-19 infection. Moreover, some of the Disease-Modifying Anti-Rheumatic Drugs (DMARDS) commonly used to treat rheumatic diseases like Hydroxychloroquine (HCQ) were proposed as a potential therapy for COVID-19 with a lack of full understanding of their molecular mechanisms. This highlights the need for the discovery of common pathways that may link both diseases at the molecular side. In this research, we used the in silico approach to investigate the transcriptomic profile of RA synovium to identify shared molecular pathways with that of severe acute respiratory syndrome-corona virus-2 (SARS-COV-2) infected lung tissue. Our results showed upregulation of chemotactic factors, including CCL4, CCL8, and CCL11, that all shared CCR5 as their receptor, as a common derangement observed in both diseases; RA and COVID-19. Moreover, our results also highlighted a possible mechanism through which HCQ, which can be used as a monotherapy in mild RA or as one of the triple-DMARDs therapy (tDMARDs; methotrexate, sulphasalazine, and HCQ), might interfere with the COVID-19 infection. This might be achieved through the ability of HCQ to upregulate specific immune cell populations like activated natural killer (NK) cells, which were found to be significantly reduced in COVID-19 infection. In addition to its ability to block CCR5 rich immune cell recruitment that also was upregulated in the SARS-COV-2 infected lungs. This might explain some of the reports that showed beneficial effects.

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C-C Chemokine Receptor Type 5 Links COVID-19, Rheumatoid Arthritis, and Hydroxychloroquine

10.21203/rs.3.rs-37404/v1 ◽

2020 ◽

Author(s):

Mahmood Yaseen HACHIM ◽

Ibrahim Y. Hachim ◽

Kashif Naeem ◽

Haifa Hannawi ◽

Issa Al Salmi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Molecular Mechanisms ◽

Immune Cell ◽

Severe Form ◽

Cell Recruitment ◽

Beneficial Effects ◽

Increased Risk ◽

Patient Groups ◽

Chemotactic Factors ◽

Immune Cell Recruitment

Abstract Background: Patients with rheumatoid arthritis (RA) represent one of the fragile patient groups that might be susceptible to coronavirus disease -19 (COVID-19) and its severe form. On the other side, RA patients have been found not to have an increased risk of COVID19 infection. Moreover, some of the Disease-Modifying Anti-Rheumatic Drugs (DMARDS) commonly used to treat rheumatic diseases like Hydroxychloroquine (HCQ) were proposed as a potential therapy for COVID19 with a lack of full understanding of their molecular mechanisms. This highlights the need for the discovery of common pathways that may link both diseases at the molecular side Methods: We used the in silico approach to investigate the transcriptomic profile of RA synovium compared to osteoarthritis and healthy controls to identify RA specific molecular pathways shared with that of severe acute respiratory syndrome-corona virus-2 (SARS-COV-2) infected lung tissue. Results: Our results showed upregulation of chemotactic factors, including CCL4, CCL8, and CCL11, that all shared CCR5 as their receptor, as a common derangement observed in both diseases; RA and COVID-19. Moreover, our results also highlighted that HCQ might interfere with the COVID-19 infection through its ability to upregulate specific immune cell populations like activated natural killer (NK) cells, besides blocking CCR5 rich immune cell recruitment to the SARS-COV-2 infected lungs Conclusion: Our results might explain some of the reports that showed beneficial effects and indicate the need for proper patients stratification on their immune profile before selecting the therapeutic protocol or clinical trial enrollment. Keyword COVID-19, SARS-COV-2, Hydroxychloroquine, rheumatoid arthritis

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C-C chemokine receptor type 5 links COVID-19, Rheumatoid arthritis, and Hydroxychloroquine

10.21203/rs.3.rs-48001/v1 ◽

2020 ◽

Author(s):

Mahmood Yaseen Hachim ◽

Ibrahim Hachim ◽

Kashif Naeem ◽

Haifa Hannawi ◽

Issa Al Salmi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Molecular Mechanisms ◽

Immune Cell ◽

Severe Form ◽

Cell Recruitment ◽

Beneficial Effects ◽

Increased Risk ◽

Patient Groups ◽

Chemotactic Factors ◽

Immune Cell Recruitment

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Targeting Melanoma-Initiating Cells by Caffeine: In Silico and In Vitro Approaches

Molecules ◽

10.3390/molecules26123619 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3619

Author(s):

Claudio Tabolacci ◽

Martina Cordella ◽

Stefania Rossi ◽

Marialaura Bonaccio ◽

Adriana Eramo ◽

...

Keyword(s):

Bioactive Compounds ◽

In Silico ◽

Molecular Mechanisms ◽

In Silico Analysis ◽

Experimental Models ◽

Conditioned Media ◽

Antiproliferative Effects ◽

Beneficial Effects ◽

Large Heterogeneity

The beneficial effects of coffee on human diseases are well documented, but the molecular mechanisms of its bioactive compounds on cancer are not completely elucidated. This is likely due to the large heterogeneity of coffee preparations and different coffee-based beverages, but also to the choice of experimental models where proliferation, differentiation and immune responses are differently affected. The aim of the present study was to investigate the effects of one of the most interesting bioactive compounds in coffee, i.e., caffeine, using a cellular model of melanoma at a defined differentiation level. A preliminary in silico analysis carried out on public gene-expression databases identified genes potentially involved in caffeine’s effects and suggested some specific molecular targets, including tyrosinase. Proliferation was investigated in vitro on human melanoma initiating cells (MICs) and cytokine expression was measured in conditioned media. Tyrosinase was revealed as a key player in caffeine’s mechanisms of action, suggesting a crucial role in immunomodulation through the reduction in IL-1β, IP-10, MIP-1α, MIP-1β and RANTES secretion onto MICs conditioned media. The potent antiproliferative effects of caffeine on MICs are likely to occur by promoting melanin production and reducing inflammatory signals’ secretion. These data suggest tyrosinase as a key player mediating the effects of caffeine on melanoma.

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POS1223 RAS GUANYL RELEASING PROTEIN 1 (RASGRP1) IN PERIPHERAL B CELLS LINKS RA TO COVID-19

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2809 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 895.2-895

Author(s):

S. Hannawi ◽

F. Alqutami ◽

M. Y. Hachim

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Plasma Cells ◽

Immune Cell ◽

In Silico Analysis ◽

Differentially Expressed ◽

Transcriptional Enhancer ◽

Activated T Cells

Background:Changes in the B cell subpopulations is a hallmark of the antiviral response against SARS-CoV-2 and is associated with COVID-19 severity (1). Recently our group showed common derangement observed in rheumatoid arthritis (RA) and COVID-19 (2). In RA, synovium attracts potentially autoreactive—B cells and plasma cells that play a central role in RA pathogenesis (3). We were interested to know the similarity in B cell’s transcriptomic changes specific to RA and COVID-19.Objectives:Identify similar upregulated genes in synovium and B cells in RA and at the same time are differentially expressed in B cells infected with SARS-CoV-2 or from COVID-19 patients.Methods:RNAseq dataset (GSE89408) of (218) samples isolated from joint synovial biopsies from subjects with and without rheumatoid arthritis were retrieved from GEO online database. Differentially expressed genes (DRGs) specific to RA were identified after exclusion of those upregulated in Osteoarthritis or other joint condition samples in the same dataset. The RA specific genes were intersected with DEGs between B cells from healthy versus RA as extracted from (GSE110999) dataset. The shortlisted genes specifically upregulated in B cells of RA were identified and were explored in B cells COVID-19 transcriptome datasets using (https://metascape.org/COVID).Results:60 genes were found to be specifically upregulated in RA synovium and B cells and are changed in B cells infected with SARS-CoV-2 or from COVID-19 patients, Figure (1-A). Those genes were involved in interferon signaling, antiviral and immune cell activation. RASGRP1 was common between B cells of RA and COVID-19 and might play a role in the pathogenesis of both, Figure (1-B). RASGRP1 controls ERK/MAPK kinase cascade needed in B-/T-cell differentiation and development. It is vital to protect against viral infection and the autoimmune associated proliferation of activated T-cells like RA (4). We checked its level in another dataset (GSE152641) of the whole blood RNASeq of 62 COVID-19 patients and 24 healthy controls. RASGRP1 was significantly down in COVID-19 compared to healthy control, Figure (1-C).Conclusion:SARS-CoV-2 impair B and T’s cells’ immune response through its action on RASGRP1 and that can be a novel mechanistic explanation of how the virus decreases immune cells and impair the B cell’s humoral immunity.References:[1]Sosa-Hernández VA, Torres-Ruíz J, Cervantes-Díaz R, Romero-Ramírez S, Páez-Franco JC, Meza-Sánchez DE, et al. B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients. Frontiers in Immunology. 2020;11(3244).[2]Hachim MY, Hachim IY, Naeem KB, Hannawi H, Al Salmi I, Hannawi S. C-C chemokine receptor type 5 links COVID-19, rheumatoid arthritis, and Hydroxychloroquine: in silico analysis. Translational Medicine Communications. 2020;5(1):14.[3]Doorenspleet ME, Klarenbeek PL, de Hair MJ, van Schaik BD, Esveldt RE, van Kampen AH, et al. Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity. Ann Rheum Dis. 2014;73(4):756-62.[4]Molineros JE, Singh B, Terao C, Okada Y, Kaplan J, McDaniel B, et al. Mechanistic Characterization of RASGRP1 Variants Identifies an hnRNP-K-Regulated Transcriptional Enhancer Contributing to SLE Susceptibility. Frontiers in Immunology. 2019;10(1066).Disclosure of Interests:None declared

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Revisiting the Metabolic Capabilities of Bifidobacterium longum susbp. longum and Bifidobacterium longum subsp. infantis from a Glycoside Hydrolase Perspective

Microorganisms ◽

10.3390/microorganisms8050723 ◽

2020 ◽

Vol 8 (5) ◽

pp. 723

Author(s):

Guillermo Blanco ◽

Lorena Ruiz ◽

Hector Tamés ◽

Patricia Ruas-Madiedo ◽

Florentino Fdez-Riverola ◽

...

Keyword(s):

In Silico ◽

Genetic Background ◽

Bifidobacterium Longum ◽

In Silico Analysis ◽

Glycoside Hydrolases ◽

Computational Tools ◽

Beneficial Effects ◽

Silico Analysis ◽

Insight Into

Bifidobacteria are among the most abundant microorganisms inhabiting the intestine of humans and many animals. Within the genus Bifidobacterium, several beneficial effects have been attributed to strains belonging to the subspecies Bifidobacterium longum subsp. longum and Bifidobacterium longum subsp. infantis, which are often found in infants and adults. The increasing numbers of sequenced genomes belonging to these two subspecies, and the availability of novel computational tools focused on predicting glycolytic abilities, with the aim of understanding the capabilities of degrading specific carbohydrates, allowed us to depict the potential glycoside hydrolases (GH) of these bacteria, with a focus on those GH profiles that differ in the two subspecies. We performed an in silico examination of 188 sequenced B. longum genomes and depicted the commonly present and strain-specific GHs and GH families among representatives of this species. Additionally, GH profiling, genome-based and 16S rRNA-based clustering analyses showed that the subspecies assignment of some strains does not properly match with their genetic background. Furthermore, the analysis of the potential GH component allowed the distinction of clear GH patterns. Some of the GH activities, and their link with the two subspecies under study, are further discussed. Overall, our in silico analysis poses some questions about the suitability of considering the GH activities of B. longum subsp. longum and B. longum subsp. infantis to gain insight into the characterization and classification of these two subspecies with probiotic interest.

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Molecular mechanisms underlying rheumatoid arthritis and cancer development and treatment

Future Oncology ◽

10.2217/fon-2019-0722 ◽

2020 ◽

Cited By ~ 1

Author(s):

Susan Morand ◽

Hannah Staats ◽

Justin Fortune Creeden ◽

Azwar Iqbal ◽

Bashar Kahaleh ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Molecular Mechanisms ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Joint Damage ◽

Cancer Development ◽

Disease Modifying Antirheumatic Drugs ◽

Growth And Survival ◽

Increased Risk ◽

Development Risk

Given recent advances in cancer immune therapy, specifically use of checkpoint inhibitors, understanding the link between autoimmunity and cancer is essential. Rheumatoid arthritis (RA) affects about 1% of the population, and early diagnosis is key to prevent joint damage. Management consists of disease-modifying antirheumatic drugs that alter normal immunologic pathways, which could affect malignancy growth and survival. Prolonged immune dysregulation and the resulting inflammatory response associated with development of RA may also lead to increased cancer development risk. RA has long been associated with increased risk of non-Hodgkin's lymphoma [ 1 ] and further evidence supports relationship to lung cancer [ 2 ]. This review will address the mechanisms behind cancer development and progression in RA patients, biomarkers and assess cancer risk and early detection.

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Chemical Profile, Antioxidant and Alpha-Amylase Inhibitory Activity of Leaves Extracts of Annona muricata: A Combined In vitro and In silico Study

Letters in Applied NanoBioScience ◽

10.33263/lianbs112.34703479 ◽

2021 ◽

Vol 11 (2) ◽

pp. 3470-3479

Keyword(s):

Molecular Docking ◽

Inhibitory Activity ◽

In Silico ◽

Molecular Mechanisms ◽

Hydrophobic Interactions ◽

In Silico Analysis ◽

Gas Chromatography Mass Spectrometry ◽

Annona Muricata ◽

Butanol Extract

Leaves of Annona muricata are commonly used for treating diabetes. This study was conducted to investigate the molecular mechanisms involved in the antidiabetic properties of leaves of Annona muricata. Leaves of Annona muricata were extracted separately with H2O, hydromethanol (50% methanol), methanol, ethylacetate, and n-butanol. Chemical characterization of the extracts was performed by spectrophotometry and Gas chromatography-Mass Spectrometry (GC-MS) techniques. Biological activity was determined by α-amylase inhibition assays and molecular docking. The hydromethanol extract had a total phenolics concentration of 117.00±0.59 µg GAE/mg extract whereas; flavonoids were most abundant in the n-butanol extract accounting for 29.34±8.87 µg QE/mg extract. The n-butanol extract had the best FRAP value of 41.17±0.57 Vit C eqv mM, which was significantly higher than the value of the vitamin C reference. Estimated IC50 for all the extracts did not differ significantly but was significantly higher than the reference compound quercetin. All extracts inhibited α-amylase in vitro albeit significantly lower than acarbose. The hydromethanol extract had the highest inhibitory activity (53.31 ± 0.33%). Furthermore, chemical profiling of the hydromethanol extract revealed the presence of a variety of bioactive compounds. In silico analysis by molecular docking of the compounds identified by GC-MS on α-amylase revealed that the compounds had robust molecular interactions orchestrated by H-bonding and hydrophobic interactions. From the results, it can be concluded that extracts of Annona muricata possess antioxidant phytochemicals that inhibit α-amylase. Therefore, the results justify the use of the plant for the treatment of diabetes.

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Tumor necrosis factor (TNF)-α- 308 G/A gene polymorphism (rs1800629) in Egyptian patients with alopecia areata and vitiligo, a laboratory and in silico analysis

PLoS ONE ◽

10.1371/journal.pone.0240221 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0240221

Author(s):

Talal Abd El-Raheem ◽

Rania H. Mahmoud ◽

Enas M. Hefzy ◽

Mohamed Masoud ◽

Reham Ismail ◽

...

Keyword(s):

Risk Factors ◽

Alopecia Areata ◽

In Silico ◽

In Silico Analysis ◽

Nucleotide Polymorphisms ◽

Sp1 Transcription Factor ◽

Increased Risk ◽

Tnf Α ◽

Egyptian Patients ◽

Subsequent Effect

Purpose & methods Several single-nucleotide polymorphisms (SNPs) in the promoter region of the TNF-α gene can cause variations in the gene regulatory sites and act as risk factors for some autoimmune disorders as alopecia areata (AA) and vitiligo. This study aimed to detect the serum TNF-α (sTNF) level (by ELISA) and the rs1800629 (by real-time PCR) among AA and vitiligo Egyptian patients and to determine their relation with disease duration and severity. In silico analysis of this SNP to study the molecular regulation of the mutant genotypes was also done. Results In AA patients, no risk was associated with the mutant genotypes vs. the normal genotype, or with A allele vs. G allele. The risk of vitiligo was significantly higher with the G/A and A/A genotypes compared with HCs (p = 0.011). Similarly, a significantly increased risk was noted in patients with A allele vs. G allele (p<0.0001). In AA and vitiligo patients, a significant increase in sTNF-α levels was noted in the mutant G/A genotypes vs. the normal G/G genotype (p<0.0001) and in the A allele vs the G allele (p<0.0001). According to the in silico analysis, this SNP could mainly affect the SP1 transcription factor binding site with subsequent effect on TNF-α expression. Conclusion According to results of the laboratory and the in silico study, the mutant TNF-α (308) genotypes were risk factors that conferred susceptibility to vitiligo among Egyptian patients but had no effect on the susceptibility to AA.

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Siblings of patients with rheumatoid arthritis have an increased mortality rate: a Swedish cohort study

RMD Open ◽

10.1136/rmdopen-2020-001197 ◽

2020 ◽

Vol 6 (1) ◽

pp. e001197

Author(s):

Helga Westerlind ◽

Bénédicte Delcoigne ◽

Johan Askling

Keyword(s):

Rheumatoid Arthritis ◽

General Population ◽

Excess Mortality ◽

Cox Regression ◽

Direct Impact ◽

Risk Of Death ◽

Increased Risk ◽

Patient Groups ◽

Swedish Cohort ◽

New Onset

ObjectivesTo estimate the mortality among siblings of patients with rheumatoid arthritis (RA) and put any excess mortality among these in relation to the mortality among patients with RA.MethodsUsing prospective nation-wide registers, we identified patients diagnosed with new-onset RA 2001–2017 (n=8137), patients with prevalent RA 2006–2017 (n=25 464), matched general population comparator subjects to all RA patients (n=22 457/68 674) and full-siblings of all groups (n=28 878/91 546).We followed all cohorts until death, 31 December 2018, migration and (for non-RA subjects) RA diagnosis. We compared patients with RA versus the general population, and siblings of RA versus siblings of the general population using Cox regression, including adjustment for socio-economy.ResultsThe HR of death versus the general population was 1.11 (95% CI 1.01 to 1.22) for incident and 1.46 (95% CI 1.39 to 1.52) for prevalent patients with RA. The siblings of these patient groups were also at increased risk of death (HR=1.10, 95% CI 1.01 to 1.20 and 1.09, 95% CI 1.04 to 1.13, respectively), with little impact of adjustment for socio-economy.ConclusionThe mortality in RA is increased, but around one-fifth of this excess is present also among their siblings. Previous literature using general population rates for comparison has thus likely overestimated the direct impact on mortality attributable to RA. To bring down excess mortality in RA, optimal disease control is important but may not suffice.

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