Silymarin: A Phytoconstituent with Significant Therapeutic Potential-A Narrative Review

Silymarin, is a phytoactive constituent isolated from the fruits and seeds of Silybum maria-num L Gaetn.), also called milk thistle belonging to the family of Asteracease. The phytoactive has been used to treat several physiological disorders. The objective of this manuscript was to review the therapeutic prospective of silymarin due to its ability to treat several physiological disorders. The da-tabases such as Pubmed, Elsevier, and Google Scholar were reviewed for the investigations or reviews published related to the title. The discussion is focused on the immunomodulatory, chemopreventive, and anti-inflammatory mechanisms of silymarin in various metabolic and dermatological disorders. In addition, the review discusses the different therapeutic potentials of silymarin such as the management of the liver disorder, skin carcinogenesis, cardiovascular disorders, diabetes mellitus, neurodegenera-tive disorders, and several dermatological disorders such as melasma, anti-aging, acne, rosacea, atopic dermatitis, and psoriasis. Silymarin is safe even with a dose higher than the therapeutic dose. Si-lymarin had good potential for the safe and effective treatment of numerous metabolic and dermatological disorders. © 2023 Bentham Science Publishers.

Computational Docking Study of the Phytochemical Constituent, Silybin (Silybum marianum) against SARS-CoV-2 Omicron Variant Spike Glycoprotein: An In-silico Approach

SARS-CoV-2 is continually evolving with the emergence of new variants with increased viral pathogenicity. The emergence of heavily mutated Omicron (B.1.1.529) with spike protein mutations are known to mediate its higher transmissibility and immune escape that has brought newer challenges for global public health to contain SARS-CoV-2 infection. One has to come up with a therapeutic strategy against the virus so as to effectively contain the infection and spread. Natural phytochemicals are being considered a significant source of bioactive compounds possessing an antiviral therapeutic potential. Being a promising anticancer and chemo-preventive agent, Silybin holds a significant potential to be used as a therapeutic. In the present study, molecular docking of Silybin with Omicron spike protein (7QNW) was carried out. Molecular docking results showed greater stability of Silybin in the active site of the Omicron spike protein with suitable binding mode of interactions. The study reveals that Silybin has the potential to block the host ACE2 receptor-viral spike protein binding;thereby inhibiting the viral entry to human cells. Therefore, Silybin may be further developed as a medication with the ability to effectively combat SARS-CoV-2 Omicron.Copyright © The Author(s) 2023.

Flavan-based phytoconstituents inhibit Mpro, a SARS-COV-2 molecular target, in silico.

A well-validated in-silico approach can provide promising drug candidates for the treatment of the ongoing CoVID19 pandemic. In this study, we have screened 32 phytochemical constituents (PCCs) with Mpro binding site (PDB:6W63) based on which we identified three possible candidates that are likely to be effective against CoVID19-viz., licoleafol (binding energy: -8.1 kcal/mol), epicatechin gallate (-8.5 kcal/mol) and silibinin (-8.4 kcal/mol) that result in higher binding affinity than the known inhibitor, X77 (-7.7 kcal/mol). Molecular dynamics (MD) simulations of PCCs-Mpro complex confirmed molecular docking results with high structural and dynamical stability. The selected compounds were found to exhibit low mean squared displacements (licoleafol: 2.25 ± 0.43 Å, epicatechin gallate: 1.93 ± 0.35 Å, and silibinin: 1.39 ± 0.19 Å) and overall low fluctuations of the binding complexes (root mean squared fluctuations below 2 Å). Visualization of the MD trajectories and structural analyses revealed that they remain confined to the initial binding region, with mean fluctuations lower than 3 Å. To access the collective motion of the atoms, we performed principal component analysis demonstrating that the first 10 principal components are the major contributors (approximate contribution of 80%) and are responsible for the overall PCCs motion. Considering that the three selected PCCs share the same flavan backbone and exhibit antiviral activity against hepatitis C, we opine that licoleafol, epi-catechin gallate, and silibinin can be promising anti-CoVID19 drug candidates.Communicated by Ramaswamy H. Sarma.

LATE ONSET PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS in AN INDIAN ADOLESCENT BOY during A PEAK of POST COVID-19 MULTISYSTEM INFLAMMATORY SYNDROME

Background: Familial Hemophagocytic lymphohistiocytosis (fHLH) categorized as FHL2 (PRF1), FHL3 (UNC13D), FHL4 (STX11), and FHL5 (STXBP2) encoding for Perforin, Munc13-4, Syntaxin11, and Syntaxin binding protein 2, respectively. There is limited information available about the clinical and mutational spectrum of FHL patients in Indian population. Objectives: To delineate clinical and laboratory features of late onset familial Hemophagocytic Lymphohistiocytosis. Methods: A 12-years-old well nourished sick looking boy, born to a non-consanguineous parents with normal birth, development and immunization history with uneventful past presented to us with 6 days history of high fever, cough, breathing difficulty and severe headache. He had occasional vomiting, abdominal pain, polyarthragia & chest pain from last 10 days. Mother also had given history of throat pain, backache & some non-specifc papular rashes over face before the onset of fever. His vitals were normal. Examination revealed faint diffuse fxed erythematous rash all over the body, pallor, icterus and hepatos-plenomegaly. Musculoskeletal examination was unremarkable. Lab evaluation revealed HB 8.9gm%, TLC 4700/cumm with neutrophils 40% and lymphocytes 56% with 8-9% activated lympocytes. Further evaluation showed low ESR 6mm/hr, fbrinogen 97mg% and albumin 2.2 gm% with elevated CRP 40mg/L, ferritin 2000ng/ml, LDH 658IU/L, SGPT 110IU/L, SGOT 221 IU/L, total bilirubin 6mg%, D-dimer 4355 ng:EFU/ml and Triglycerides 441mg%. His blood, urine, CSF and bone marrow cultures were sterile for endemic bacterial and viral infections in our area. His EBV PCR, CoVID RT PCR and CoVID antibody (Total & IgG) test were negative. His immunoglobulin leves were normal. HRCT Chest showed bilateral mild-moderate plural effusions, mild interstitial thickening in both the lower lobes, few fbrotic opacities & old areas of consolidation bilaterally. 2D echo showed mild pericardial effusion. Bone marrow examination showed Hypercellular marrow with iron depletion and occasional hemophagocytosis with CD8 T lymphocytes proliferation (55.2%) and double positive CD4 & CD8 (1.2%). He was initially commenced on supportive therapy, oxygen & intravenous antibiotics. In view of most probable non-infectious, non-malignant hemophagocytic lymphohistiocytosis, he was fnally given intravenous immunoglobulin (2gm/kg) and intravenous pulse methylprednisolone (30mg/kg). He responded well to above regimen within 3 days. He was discharged with tapering steroids over few weeks. Clinical exome by NGS revealed Homozygous Mutation in STXBP2 gene Intron 14, c.1280-1G>C (3' Splice Site) His parents has been counselled for hematopoietic stem cell transplantation and their decision is still pending. Results: We compared our patietnt with a reference to the largest Indian series of pediatric HLH1. Conclusion: Primary HLH type 5 can present frst time during childhood and adolescence. Any child presenting with unexplained HLH features should undergo genetic analysis irrespective of person's past and family history.

The favorable impacts of silibinin polyphenols as adjunctive therapy in reducing the complications of COVID-19: A review of research evidence and underlying mechanisms.

The proceeding pandemic of coronavirus disease 2019 is the latest global challenge. Like most other infectious diseases, inflammation, oxidative stress, and immune system dysfunctions play a pivotal role in the pathogenesis of COVID-19. Furthermore, the quest of finding a potential pharmaceutical therapy for preventing and treating COVID-19 is still ongoing. Silymarin, a mixture of flavonolignans extracted from the milk thistle, has exhibited numerous therapeutic benefits. We reviewed the beneficial effects of silymarin on oxidative stress, inflammation, and the immune system, as primary factors involved in the pathogenesis of COVID-19. We searched PubMed/Medline, Web of Science, Scopus, and Science Direct databases up to April 2022 using the relevant keywords. In summary, the current review indicates that silymarin might exert therapeutic effects against COVID-19 by improving the antioxidant system, attenuating inflammatory response and respiratory distress, and enhancing immune system function. Silymarin can also bind to target proteins of SARS-CoV-2, including main protease, spike glycoprotein, and RNA-dependent RNA-polymerase, leading to the inhibition of viral replication. Although multiple lines of evidence suggest the possible promising impacts of silymarin in COVID-19, further clinical trials are encouraged.

Comparative evaluation of flavonoids reveals the superiority and promising inhibition activity of silibinin against SARS-CoV-2.

Flavonoids are phenolic compounds naturally found in plants and commonly consumed in diets. Herein, flavonoids were sequentially evaluated by a comparative in silico study associated with systematic literature search. This was followed by an in vitro study and enzyme inhibition assays against vital SARS-CoV-2 proteins including spike (S) protein, main protease (Mpro ), RNA-dependent RNA-polymerase (RdRp), and human transmembrane serine protease (TMPRSS2). The results obtained revealed 10 flavonoids with potential antiviral activity. Out of them, silibinin showed promising selectivity index against SARS-CoV-2 in vitro. Screening against S protein discloses the highest inhibition activity of silibinin. Mapping the activity of silibinin indicated its excellent binding inhibition activity against SARS-CoV-2 S protein, Mpro and RdRP at IC50 0.029, 0.021, and 0.042 µM, respectively, while it showed no inhibition activity against TMPRSS2 at its IC50(SARS-CoV-2) . Silibinin was tested safe on human mammalian cells at >7-fold its IC50(SARS-CoV-2) . Additionally, silibinin exhibited >90% virucidal activity at 0.031 µM. Comparative molecular docking (MD) showed that silibinin possesses the highest binding affinity to S protein and RdRP at -7.78 and -7.15 kcal/mol, respectively. MDs showed that silibinin exhibited stable interaction with key amino acids of SARS-CoV-2 targets. Collectively, silibinin, an FDA-approved drug, can significantly interfere with SARS-CoV-2 entry and replication through multi-targeting activity.

Clinical Management of COVID-19 in Cancer Patients with the STAT3 Inhibitor Silibinin.

COVID-19 pathophysiology is caused by a cascade of respiratory and multiorgan failures arising, at least in part, from the SARS-CoV-2-driven dysregulation of the master transcriptional factor STAT3. Pharmacological correction of STAT3 over-stimulation, which is at the root of acute respiratory distress syndrome (ARDS) and coagulopathy/thrombosis events, should be considered for treatment of severe COVID-19. In this perspective, we first review the current body of knowledge on the role of STAT3 in the pathogenesis of severe COVID-19. We then exemplify the potential clinical value of treating COVID-19 disease with STAT3 inhibitors by presenting the outcomes of two hospitalized patients with active cancer and COVID-19 receiving oral Legalon®-a nutraceutical containing the naturally occurring STAT3 inhibitor silibinin. Both patients, which were recruited to the clinical trial SIL-COVID19 (EudraCT number: 2020-001794-77) had SARS-CoV-2 bilateral interstitial pneumonia and a high COVID-GRAM score, and showed systemic proinflammatory responses in terms of lymphocytopenia and hypoalbuminemia. Both patients were predicted to be at high risk of critical COVID-19 illness in terms of intensive care unit admission, invasive ventilation, or death. In addition to physician's choice of best available therapy or supportive care, patients received 1050 mg/day Legalon® for 10 days without side-effects. Silibinin-treated cancer/COVID-19+ patients required only minimal oxygen support (2-4 L/min) during the episode, exhibited a sharp decline of the STAT3-regulated C-reactive protein, and demonstrated complete resolution of the pulmonary lesions. These findings might inspire future research to advance our knowledge and improve silibinin-based clinical interventions aimed to target STAT3-driven COVID-19 pathophysiology.

Silibinin as potential tool against SARS-Cov-2: In silico spike receptor-binding domain and main protease molecular docking analysis, and in vitro endothelial protective effects.

The spread of SARS-CoV-2, along with the lack of targeted medicaments, encouraged research of existing drugs for repurposing. The rapid response to SARS-CoV-2 infection comprises a complex interaction of cytokine storm, endothelial dysfunction, inflammation, and pathologic coagulation. Thus, active molecules targeting multiple steps in SARS-CoV-2 lifecycle are highly wanted. Herein we explored the in silico capability of silibinin from Silybum marianum to interact with the SARS-CoV-2 main target proteins, and the in vitro effects against cytokine-induced-inflammation and dysfunction in human umbilical vein endothelial cells (HUVECs). Computational analysis revealed that silibinin forms a stable complex with SARS-CoV-2 spike protein RBD, has good negative binding affinity with Mpro, and interacts with many residues on the active site of Mpro, thus supporting its potentiality in inhibiting viral entry and replication. Moreover, HUVECs pretreatment with silibinin reduced TNF-α-induced gene expression of the proinflammatory genes IL-6 and MCP-1, as well as of PAI-1, a critical factor in coagulopathy and thrombosis, and of ET-1, a peptide involved in hemostatic vasoconstriction. Then, due to endothelium antiinflammatory and anticoagulant properties of silibinin and its capability to interact with SARS-CoV-2 main target proteins demonstrated herein, silibinin could be a strong candidate for COVID-19 management from a multitarget perspective.