Macrophages are critical mediators of the innate immune response against foreign pathogens, including bacteria, physical stress, and injury. Therefore, these cells play a key role in the ..."inflammatory pathway" which in turn can lead to an array of diseases and disorders such as autoimmune neuropathies and myocarditis, inflammatory bowel disease, atherosclerosis, sepsis, arthritis, diabetes, and angiogenesis. Recently, more studies have focused on the macrophages inflammatory diseases since the discovery of the two subtypes of macrophages, which are differentiated on the basis of their phenotype and distinct gene expression pattern. Of these, M1 macrophages are pro-inflammatory and responsible for inflammatory signaling, while M2 are anti-inflammatory macrophages that participate in the resolution of the inflammatory process, M2 macrophages produce anti-inflammatory cytokines, thereby contributing to tissue healing. Many studies have shown the role of these two subtypes in the inflammatory pathway, and their emergence appears to decide the fate of inflammatory signaling and disease progression. As a next step in directing the pro-inflammatory response toward the anti-inflammatory type after an insult by a foreign pathogen (e. g., bacterial lipopolysaccharide), investigators have identified many natural compounds that have the potential to modulate M1 to M2 macrophages. In this review, we provide a focused discussion of advances in the identification of natural therapeutic molecules with anti-inflammatory properties that modulate the phenotype of macrophages from M1 to M2.
Background and objective
Coronavirus disease (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the incessant spread of the disease with ...substantial morbidity and mortality rates, there is an urgent demand for effective therapeutics and vaccines to control and diminish this pandemic. A critical step in the crosstalk between the virus and the host cell is the binding of SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cells. Hence, inhibition of this interaction could be a promising strategy to combat the SARS-CoV-2 infection.
Methods
Docking and Molecular Dynamics (MD) simulation studies revealed that designed peptide maintains their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2.
Results
We have designed a novel peptide that could inhibit SARS-CoV-2 spike protein interaction with ACE2, thereby blocking the cellular entry of the virus.
Conclusion
Our findings suggest that computationally developed inhibitory peptide may be developed as an anti-SARS-CoV-2 agent for the treatment of SARS-CoV-2 infection. We further plan to pursue the peptide in cell-based assays and eventually for clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The outbreak of the coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 triggered a global pandemic where control is needed through therapeutic and preventive ...interventions. This study aims to identify natural compounds that could affect the fusion between the viral membrane (receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein) and the human cell receptor angiotensin-converting enzyme 2. Accordingly, we performed the enzyme-linked immunosorbent assay-based screening of 10 phytochemicals that already showed numerous positive effects on human health in several epidemiological studies and clinical trials. Among these phytochemicals, epigallocatechin gallate, a polyphenol and a major component of green tea, could effectively inhibit the interaction between the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein and the human cell receptor angiotensin-converting enzyme 2. Alternately,
in silico
molecular docking studies of epigallocatechin gallate and angiotensin-converting enzyme 2 indicated a binding score of −7.8 kcal/mol and identified a hydrogen bond between R393 and angiotensin-converting enzyme 2, which is considered as a key interacting residue involved in binding with the severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain, suggesting the possible blocking of interaction between receptor-binding domain and angiotensin-converting enzyme 2. Furthermore, epigallocatechin gallate could attenuate severe acute respiratory syndrome coronavirus 2 infection and replication in Caco-2 cells. These results shed insight into identification and validation of severe acute respiratory syndrome coronavirus 2 entry inhibitors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Centrins are cytoskeletal proteins associated with the centrosomes or basal bodies in the eukaryotes. We previously reported the involvement of Centrin 1–3 proteins in cell division in the protozoan ...parasites Leishmania donovani and Trypanosoma brucei. Centrin4 and 5, unique to such parasites, had never been characterized in Leishmania parasite. In the current study, we addressed the function of centrin4 (LdCen4) in Leishmania. By dominant-negative study, the episomal expression of C-terminal truncated LdCen4 in the parasite reduced the parasite growth. LdCen4 double allele gene deletion by either homologous recombination or CRISPR-Cas9 was not successful in L. donovani. However, CRISPR-Cas9-based deletion of the homologous gene was possible in L. mexicana, which attenuated the parasite growth in vitro, but not ex vivo in the macrophages. LdCen4 also interacts with endogenous and overexpressed LdPOC protein, a homolog of centrin reacting human POC (protein of centriole) in a calcium sensitive manner. LdCen4 and LdPOC binding has also been confirmed through in silico analysis by protein structural docking and validated by co-immunoprecipitation. By immunofluorescence studies, we found that both the proteins share a common localization at the basal bodies. Thus, for the first time, this article describes novel centrin4 and its binding protein in the protozoan parasites.
•Centrin4 isoform is unique to trypanosomatid family members that cause several human infections.•Centrin4 in Leishmania is localized at the basal body region and it's C-terminal region is important for parasite growth.•Experiments confirm that centrin4 protein in Leishmania interacts with the basal body co-expressing protein of centriole (POC).•The in silico modelled LdPOC protein of Leishmania donovani shows eight alpha helices and seven loop structures.
Inflammation is set off when innate immune cells detect infection or tissue injury. Tight control of the severity, duration, and location of inflammation is an absolute requirement for an appropriate ...balance between clearance of injured tissue and pathogens versus damage to host cells. Impeding the risk associated with the imbalance in the inflammatory response requires precise identification of potential therapeutic targets involved in provoking the inflammation. Toll-like receptors (TLRs) primarily known for the pathogen recognition and subsequent immune responses are being investigated for their pathogenic role in various chronic diseases. A mammalian homologue of Drosophila Toll receptor 4 (TLR4) was shown to induce the expression of genes involved in inflammatory responses. Signaling pathways via TLR4 activate various transcription factors like Nuclear factor kappa-light-chain-enhancer (NF-κB), activator protein 1 (AP1), Signal Transducers and Activators of Transcription family of transcription factors (STAT1) and Interferon regulatory factors (IRF's), which are the key players regulating the inflammatory response. Inhibition of these targets and their upstream signaling molecules provides a potential therapeutic approach to treat inflammatory diseases. Here we review the therapeutic targets involved in TLR-4 signaling pathways that are critical for suppressing chronic inflammatory disorders.
•Tight control of the severity, duration and location of inflammation is an absolute requirement for an appropriate balance between clearance of injured tissue and pathogens versus damage to host cells.•Potential therapeutic targets involved in provoking the inflammation include Toll-like receptors (TLRs) and their downstream signaling molecules responsible for their critical role in various chronic inflammatory diseases.•Signaling pathways via TLR4 activate various transcription factors like NF-κB, AP1, STAT1, and IRFs. Inhibition of these targets and their upstream signaling molecules provide a potential therapeutic approach to treat inflammatory diseases.•In this article, we have highlighted the already known inflammatory signaling players and discussed about the recent advancements in discovery of potential targets within the major TLR-4 mediated pathway.•SiR4 activs like nuclear factor kappa-light-chain-enhancer (NF-κB), activator protein 1 (AP1), signal transducers and activators of tran(STAT1) and nterferon regulatory factors (IRF's),
Matrix metalloproteinases (MMPs) are proteinases capable of degrading components of the extracellular matrix and numerous nonmatrix proteins. MMPs along with tissue inhibitors of MMPs, have been ...implicated in the pathogenesis of liver diseases. Although, the precise mechanism-of-actions of MMPs in various liver related disorders is largely unknown, however, data from diverse experimental models indicate that these proteinases influence cellular activities including proliferation and survival, gene expression, as well as multiple aspects of inflammation. Hence, MMP's are likely key players in the outcomes related to liver disease.
Endemic seasonal coronaviruses cause morbidity and mortality in a subset of patients, but no specific treatment is available. Molnupiravir is a promising pipeline antiviral drug for treating ...SARS-CoV-2 infection potentially by targeting RNA-dependent RNA polymerase (RdRp). This study aims to evaluate the potential of repurposing molnupiravir for treating seasonal human coronavirus (HCoV) infections. Molecular docking revealed that the active form of molnupiravir, β-D-N4-hydroxycytidine (NHC), has similar binding affinity to RdRp of SARS-CoV-2 and seasonal HCoV-NL63, HCoV-OC43 and HCoV-229E. In cell culture models, treatment of molnupiravir effectively inhibited viral replication and production of infectious viruses of the three seasonal coronaviruses. A time-of-drug-addition experiment indicates the specificity of molnupiravir in inhibiting viral components. Furthermore, combining molnupiravir with the protease inhibitor GC376 resulted in enhanced antiviral activity. Our findings highlight the great potential of repurposing molnupiravir for treating seasonal coronavirus infected patients.
•Successfully modelled the RdRp structure of three seasonal coronaviruses.•Molnupiravir has similar binding affinity to the RdRp of SARS-CoV-2 and seasonal coronaviruses shown by molecular docking.•Molnupiravir effectively inhibited viral replication and production of infectious viruses of seasonal coronaviruses.•The combination of molnupiravir with the protease inhibitor GC376 resulted in enhanced antiviral activity.
Hepatic stellate cells (HSCs) are known to play a key role in the progression of liver fibrosis by producing excessive extracellular matrix (ECM). Matrix metalloproteinases (MMPs) belong to a family ...of endopeptidases, which have a well-established role in the degradation of ECM. Our study suggests that, besides the degradation of the extracellular matrix, matrix metalloproteinase-8 (MMP-8) has a non-canonical role in activating the quiescent HSCs to myofibroblasts by regulating the expression of Col1A1 and αSMA. We have identified that MMP-8 secreted from macrophages as a response to LPS stimulation activates HSCs via ERK1/2-dependent pathway. In addition to this, we determined that MMP-8 may regulate the homodimerization of c-Jun in LX-2 cells, during the trans-differentiation process from quiescent HSC to activate myofibroblasts. Macrophage-released MMP-8 plays a master role in activating the dormant HSCs to activate myofibroblasts through the Erk-mediated pathway and Jun cellular translocation leading to liver fibrosis. Significance MMP-8 can be used as a therapeutic target against liver fibrosis.
Atherosclerosis is a chronic inflammatory disease arising due to an imbalance in lipid metabolism and maladaptive immune response driven by the accumulation of cholesterol‐laden macrophages in the ...artery wall. Interactions between monocytes/macrophages and endothelial cells play an essential role in the pathogenesis of atherosclerosis. In our current study, nitric oxide synthase 1 (NOS1)‐derived nitric oxide (NO) has been identified as a regulator of macrophage and endothelial cell interaction. Oxidized LDL (OxLDL) activates NOS1, which results in the expression of CD40 ligand in macrophages. OxLDL‐stimulated macrophages produce some soluble factors which increase the CD40 receptor expression in endothelial cells. This increases the interaction between the macrophages and endothelial cells, which leads to an increase in the inflammatory response. Inhibition of NOS1‐derived NO might serve as an effective strategy to reduce foam cell formation and limit the extent of atherosclerotic plaque expansion.
► Compressive properties of aluminum honeycomb core have been investigated experimentally. ► The local deformations of the core have been studied through Digital Image Correlation. ► The out-of-plane ...direction of the core was found as the strongest direction. ► Among the in-plane properties, ribbon direction was two times stronger than the transverse direction. ► The local plastic deformation around shear band was found relatively higher than the global strains.
In-plane and out-of-plane crushing properties of the honeycomb core were investigated experimentally and with Digital Image Correlation. The out-of-plane direction of the core was found as the strongest direction which absorbed significant amount of energy during deformation. The ribbon direction was found two times stronger as compared to the transverse direction. Local deformation response in in-plane crushing was analyzed with Digital Image Correlation. It was found that the local plastic strain in the core was mainly in the shear band regime. Additionally, the local plastic strain was found higher as compared to the global stress level. The combination of experimental and Digital Image Correlation results worked excellently well in the determination of global and local deformation mechanism of the honeycomb core.
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