key: cord-0917023-pf8wo8dq
authors: Husaini, Amjad M.; Jan, Khan Nadiya; Wani, Gowher A.
title: Saffron: A potential drug-supplement for severe acute respiratory syndrome coronavirus (COVID) management
date: 2021-05-14
journal: Heliyon
DOI: 10.1016/j.heliyon.2021.e07068
sha: 12309db5a158051cd028eb920e9adaca9432a852
doc_id: 917023
cord_uid: pf8wo8dq

Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 (COVID-19), came as a significant health care challenge for humans in 2019-20. Based on recent laboratory and epidemiological studies, a growing list of mutations in the virus has the potential to enhance its transmission or help it evade the immune response. To further compound the problems, there are considerable challenges to the availability of effective, affordable, safe vaccines on a mass scale. These impediments have led some to explore additional options available in traditional medicines, especially immune-boosting natural products. Saffron has been used for centuries to treat fever, bronchitis, cold and other immune, respiratory disorders. Herein, we discuss the potential role of saffron during and after COVID-19 infection, focusing on immunomodulation, respiratory, renal, and cardiovascular functions. As a nutraceutical or drug supplement, it can alleviate the magnitude of COVID-19 symptoms in patients. The anti-inflammatory, antioxidant, and other medicinal properties attributed to saffron bioactive compounds can help in both pre-and post- infection management strategies. The abnormalities associated with COVID-19 survivors include anxiety, depression, sleep disturbances, and post-traumatic stress disorder. Saffron can help manage these post-hospitalization abnormalities (sub-acute and chronic) too, owing to its anti-depressant property. It can help common people boost immunity and manage depression, stress and anxiety caused due to prolonged lockdown, isolation or quarantine.

.

In this paper, we highlight the properties of saffron (Figure 1 ) that could help alleviate the symptoms of SARS-CoV-2 infection in light of its pathophysiology, making it a suitable candidate as a drug supplement. The purpose is not to present saffron as a solution to , but only to explore its use in the integrated management of COVID-19. It needs to be evaluated for its potential role in the long-term physical and mental health management strategy of COVID-19 patients. The paper highlights its potential use in helping manage depression, stress, and anxiety caused due to prolonged lockdowns and isolation or quarantine of people during pandemics.

The immune responses to viral infections are of two types, Innate Immune Response and Adaptive Immune Response. The major components involved in the innate immune response are Toll-like receptors (TLR) (Jiang et al., 2005) , RIG-I-like receptors (retinoic acidinducible protein 1 like) (RLR) (He et al., 2005) , Nucleotide-binding and oligomerization Domain (NOD)-like receptors (NLR) (Yu et al., 2020) , C-type lectin-like receptor (CLR) (Cui et al., 2019) , Dendritic Cell (DC) (Ziebuhr et al., 2000) . TLRs recognize pathogenassociated molecular patterns (PAMP) and target viral lipids, lipoproteins, proteins, and nucleic acids in cell membrane (TLR-2 and TLR-4), cytoplasm (TLR-3, TLR7/8), endosome, lysosome, and endocytolysosome. RLRs recognize viral RNA in the cytoplasm and cause induction of type 1 IFN and inflammatory cytokines to block viral replication (reviewed in Florindo et al., 2020) . The major components of Adaptive Immune Response are the T cells and the Humoral immune response. In T-cell mediated response, CD4 + T cells promote the production of virus-specific antibodies by activating T-dependent B cells, which produce proinflammatory cytokines via NF-kB pathway. Cytotoxic CD8 + T cells infiltrate into the infected area and eliminate viral infected cells (Lauer et al., 2020) . In the humoral immune response, activation of B cells by CD4 + T cells, memory, and antibodies secreting cells occur, targeting viral proteins through IgM, IgG, and IgA antibody production (Li et al., 2020; Bai et al., 2020) .

The host response to SARS-CoV-2 begins with the initial physiological immune response followed by the pathogenic hyperinflammatory phase. The physiological host response encompasses viral entry, infection, and the early immune phase. It involves the entry of J o u r n a l P r e -p r o o f SARS-CoV-2 into alveolar epithelial cells by binding to angiotensin-converting enzyme 2 (ACE2) through surface spike (S) protein-mediated by transmembrane serine protease 2 (TMPRSS2) (Hoffmann et al. 2020) . It is then followed by active replication and viral release, causing pyroptosis. Viral-mediated cell death causes the release of various damageassociated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). These are recognized by pattern-recognition receptors on alveolar macrophages and endothelial cells. PAMPs are recognized in the extracellular space by Toll-like receptors (TLRs), causing induction of pro-inflammatory cytokine transcription factors such as NF-κβ, while DAMPs are recognized intracellularly by nucleotide-binding domain leucine-rich repeat (NLR) proteins causing activation of inflammasomes and conversion of pro-IL-1β to active-IL-1β (Huang et al. 2020; Schnappauf et al. 2019; Soy et al. 2020) . The DAMP/PAMPs recognition causes the release of pro-inflammatory cytokine and chemokine, activation of inflammasomes, and the recruitment of monocytes, macrophages, and virusspecific T cells to eliminate the infected cells (Bohn et al. 2020) .

A more severe pathological phase follows the physiological phase in about 20 percent of infectious cases (Parasher, 2020) . It is marked by an increased secretion of pro-inflammatory cytokines and chemokines, like interleukins (IL-1, IL-6, IL-8, IL-12, and IL-120), tumour necrosis factors (TNF-α, IFN-β and IFN-λ), C-X-C motif chemokine ligand 10 (CXCL10), macrophage inflammatory protein-1α (MIP-1α), monocyte chemo-attractant protein-1 (MCP-1) and interferon gamma-induced protein 10 (IP-10) (Huang et al. 2020; Zhou et al. 2020a; Qin et al. 2020) . The cytokine surge serves as a chemo-attractant for neutrophils, CD4 helper T cells, and CD8 cytotoxic T cells, causing excessive infiltration of immune cells in the lungs. CD4 helper T cells activate B cells for producing virus-specific antibodies, while CD8 T cells kill the virus-infected cells.

In addition to ACE2, SARS-CoV-2 can also bind to dendritic-cell specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and DC-SIGN-related protein (DC-SIGNR, L-SIGN) (Jeff ers et al. 2004; Marzi et al. 2004; Yang et al. 2004) . DC-SIGN is highly expressed on dendritic cells and macrophages. Dendritic cells (DCs) are involved in phagocytosis of virus in the lungs. After phagocytosis, DCs migrate to lymphoid organs and activate antigen-specific T cells, which move into the lungs and destroy virus-infected alveolar cells. DCs, macrophages, pathological cytotoxic T cells derived from CD4 helper T cells help fight the virus, but eventually cause lung inflammation and injury [Fang et al. 2012; Small et al. 2001 ]. The host cells undergo apoptosis releasing new viral particles. The J o u r n a l P r e -p r o o f cycle of infection and apoptosis continues, leading to the loss of pneumocytes which are involved in the gas exchange between the alveoli and blood. This causes diffuse alveolar damage, and eventually results in an acute respiratory distress syndrome (Bohn et al. 2020 ).

This may then progress to activation of a procoagulant response, multiple organ failure and death, especially in old aged, immune-compromised, or with underlying pathology (Gautam et al. 2020) (Figure 2 ).

While uncontrolled immunity causes pulmonary tissue damage and reduced lung capacity, immune insufficiency or misdirection increases viral replication and tissue damage. Therefore, the induction of a balanced host immune response against SARS-CoV-2 is critical for controlling its infection (Florindo et al., 2020) . Some herbs are traditionally known to contain components that stabilize the functioning of innate immunity (macrophages, neutrophils, and dendritic cells) as well as acquired immunity (T cells and B cells).

The healing properties of saffron are recorded in Materia Medica by Pedanio Dioscorides, a

Greek medical practitioner of the first century A.D. Physicians like Hippocrates and Pliny have used it in cases of excessive drunkenness, loss of male potency, and as an aphrodisiac.

Modern medicine has acknowledged several therapeutic effects and pharmaceutical applications of saffron.

Medicinal properties of saffron are attributed to the presence of volatile as well as nonvolatile aroma yielding compounds. The red stigmas of Crocus sativus accumulate different bioactive compounds amongst which safranal, crocin, campherol, picrocrocin, crocetin, αand β-carotenes are of prime importance. The ability to synthesize these compounds is not common across species. Picrocrocin and crocin have been detected only in saffron (Crocus species), Buddleja (Liao et al., 1999), and Gardenia (Pfisteret al., 1996) .

Research on the physicochemical and biochemical properties of saffron along with the bioactivity of its compounds, has confirmed its role in pharmacognosy (Table 1) . A vast number of papers have been published focusing on cancer, antioxidant properties, sedative effect, neuronal injury, etc. (reviewed in Premkumar and Ramesh, 2010; Licón et al., 2010; Mokhtari-Zaer et al., 2020) . Saffron and its constituents are considered an efficient treatment for coronary artery diseases, neurodegenerative disorders, bronchitis, asthma, diabetes, fever, and colds (Boskabady and Farkhondeh, 2016) . It is a promising natural medicine in treating metabolic syndrome (Razavi and Hosseinzadeh, 2017) . It is a potent natural antioxidant used J o u r n a l P r e -p r o o f in folk medicine to treat cold, scarlet fever, and asthma (Boskabady and Farkhondeh, 2016; Boskabady et al., 2019) . Several in vivo studies have confirmed the antioxidant and antiinflammatory role of ethanol or aqueous extracts of saffron, safranal, and crocin (Hosseinzadeh and Younesi, 2002; Hosseinzadeh and Ghenaati, 2006) . Chatterjee et al. (2005) reported crocin to be a more potent antioxidant agent than α tocopherol. Reduction of blood bilirubin level and decreased blood cholesterol and triglycerides after using crocetin and crocin have also been reported (Nair et al., 1991) . The anticancer properties of saffron have also been reported (Duke, 1987; Abdullaev and Espinosa-Aguirre, 2004) .

Coronavirus is known to act more severely on individuals with weak immunity. The major pathway of cell destruction in COVID-19 patients is mostly immune-mediated apoptosis.

Therefore a robust immune system can help reduce the severity of the viral infection and subsequent disease response. Since ACE2 receptor is found in multiple organs viz. oral and nasal mucosa, lungs, stomach, intestine, bladder, heart, and kidney (Zhou et al. 2020b; Xu et al. 2020; Donoghue et al. 2000) , cell-mediated immunity causes damage through cytokine storm (Williams and Chambers 2014; Cameron et al. 2008) . It could be helpful if inflammation is suppressed during this severe stage (Shi et al. 2020 ). Immunity-boosting medicinal plants can help during the early non-severe stage, while herbs with antiinflammatory and anti-thrombotic properties can help during a later or severe stage (Gautam et al. 2020) . The potential role of saffron and its constituents and the possible action mechanism is described under relevant heads in the following sub-sections.

Saffron has been included by Unani medicine among the drugs used during the epidemic.

Stamen of saffron can be used as a fumigant for sanitizing the environment due to the antimicrobial activity of its volatile oils. Ibn-Rushd (1126-1198 CE), a great scholar born in Spain commonly known by the name Averroes, describes a medicine that he claims a savior during an epidemic as 'whoever has used this formulation during an epidemic remained protected from it.' The composition of this medicine is as follows: Two parts of saffron along with Aleovera L. and Commiphora myrrha Nees Engl. one part each (Nikhat and Fazil 2020) .

Both traditional and experimental evidence suggests the possible therapeutic effect of saffron and its constituents on various aspects of health, which can be helpful in the management of J o u r n a l P r e -p r o o f SARS-CoV-2 pandemic as well (Table 2) . Ancient Iranian physician, Avicenna, has stated that saffron oil can facilitate breath and strengthen the respiratory organs. Four cumulative concentrations of a hydro-ethanolic extract of saffron and its constituent safranal were tested on guinea pig tracheal smooth muscle, and the effect was found to be comparable to that of theophylline (Boskabady, 2006; Boskabady et al., 2019; Mokhtari-Zaer, 2015) . Even saffron petal extract (SPE) has been found useful through photochemical analysis, revealing the presence of flavonoids, anthocyanins, and tannins. The SPE was injected intra-peritoneally to rats for 14 days, and the results showed an increase in the number of white blood cells and antibody response without any alteration in hematological parameters (Babaei et al., 2014).

Currently, immunomodulatory drugs that target interleukins, like tocilizumab (an IgG1 monoclonal antibody against IL-6 receptor) are reported to be beneficial in moderate-tosevere cases of SARS-CoV-2 infection. Bioactive constituents of saffron can affect both cellular and humoral immunity functions, which can be quite beneficial (Table 2) .

Immunomodulation by these saffron components can help as a management strategy against SARS-CoV-2. Its immunomodulatory activity may involve direct targeting of Toll-like receptors (TLRs), attributed to nuclear factor (NF-κB), activator protein 1 (AP-1), and downstream signaling pathways (reviewed in Zeinali et al., 2019; Boskabady et al., 2020) . A randomized, double-blind placebo-controlled clinical trial has been conducted to determine the immunomodulatory effects of saffron. It was observed that saffron increases the IgG level and decreases the IgM level compared with baseline and placebo. Furthermore, it increases the percentage of monocytes in comparison to placebo. Hence, the sub-chronic daily use of 100 mg saffron was suggested to have temporary immune-modulatory activities without any adverse effects (Kianbakht and Ghazavi, 2011) . Saffron has been shown to enhance IFN-γ to IL-4 ratio in human lymphocytes and thereby affect Th1 and Th2 balance in them . These properties could aid in modulating the immune response during SARS-CoV-2 infection. A study on sensitized guinea-pigs has shown that the total and differential count of white blood cells (WBC) gets affected positively by the saffron extract and safranal (Bayrami and Boskabady, 2012) . Azithromycin is a preferred antibiotic in SARS-CoV-2 management due to its anti-inflammatory action, and the prevention of secondary bacterial infection (Parasher 2020) . Saffron has been shown to reduce inflammation by inhibiting cyclooxygenase enzyme activity (Rahmani et al., 2017) . This J o u r n a l P r e -p r o o f property can help tackle excessive lung inflammation in SARS-CoV-2 patients due to the release of pro-inflammatory cytokines and chemokines.

In traditional medicine, saffron has been used to treat fever, bronchitis, cold, pertussis, asthma, and respiratory function improvement. Safranal, a major component of saffron, might be useful in treating respiratory disorders, mostly chronic bronchitis. It has significant therapeutic effects on lung pathology and tracheal hyper-responsiveness (Boskabady et al., 2012 (Boskabady et al., , 2014 . Saffron can be useful in SARS-CoV-2 management as it has been shown to inhibit the release of inflammatory cytokine, and production of nitric oxide and nitrite (Boskabady et al., 2014) , endotheline-1, and total protein secretion (Gholamnezhad et al., 2013) , and the recruitment of inflammatory cells to the lungs in sensitized guinea pigs (Mahmoudabady et al., 2013) . Additionally, it sedates coughing through an anesthetic effect on the vagal nerves of the alveoli (Giaccio, 2004) . Byrami et al. (2013) demonstrated the preventive effects of the saffron extract on tracheal responsiveness and plasma levels of IL-4, and it was found that the saffron extract shows mild activity while crocin and picrocrocin indicated significant anti-HSV-1 and anti-HIV-1 activities. Both crocin and picrocrocin were found to be effective for inhibiting the virus entry as well as its replication.

Further, it has been suggested that crocin and picrocrocin are promising anti-HSV and anti-HIV agents for herbal therapy against viral infections (Soleymani et al., 2018) . Crocin and picrocrocin prevented the virus from entering the Vero cell, which disrupted the virus entry mechanism.

Recently, in silico analysis for pharmacokinetic, toxicological, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters of saffron bioactive molecules indicated that crocetin has a high drug score against SARS-CoV-2 (Kordzadeh et al. 2020 ) .

It was elucidated that crocin and crocetin possess a high binding affinity towards the main protease (PDB ID: 6M03) of SARS-CoV-2, and crocetin shows translocation through lipid bilayer as a drug molecule.

There are several long-term residual effects of SARS-CoV-2 infection. According to a posthospitalisation COVID-19 study, four in five patients with COVID-19 have persistent symptoms and continue to experience negative impacts on their physical and mental health, as well as ability to work (UKRI). The long-term effects include fatigue, dyspnea, cognitive problems, depression, sleep abnormalities, and deterioration in the quality of life (Carfi et al., 2020; Tenforde et al. 2020; Huang et al. 2021; Chopra et al. 2020 ). These long-term effects can be categorized into: (1) subacute abnormalities present from 1-3 months beyond acute COVID-19; and (2) chronic abnormalities persisting beyond 3 months of the onset of acute COVID-19 (Greenhalgh et al. 2020; Shah et al. 2021) . Saffron can be a suitable candidate for the management of these long-term effects. There are many safety studies of saffron where double-blind randomized trials focused on the patients with neuropsychiatric problems (Table 3) . It has been reported to be more effective than placebo or almost equivalent to the therapeutic doses of fluoxetine and imipramine (Kafi et al., 2018; Gohari et al., 2013; Qadir et al., 2020) (Table 2 , 3). Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) antidepressant, helpful as a drug for people with depression, anxiety, panic, or obsessivecompulsive symptoms (Meltzer et al., 1979) . Imipramine is a tricyclic anti-depressant (TCA) used mainly in treating depression, anxiety, panic disorder, and bedwetting (Post et al., 1974) . 

Relaxant effect of Crocus sativus (saffron) on guinea-pig tracheal chains and its possible mechanisms

Anti-inflammatory, antioxidant, and immunomodulatory effects of Crocus sativus L. and its main constituents

The effect of safranal, a constituent of Crocus sativus (saffron), on tracheal responsiveness, serum levels of cytokines, total NO and nitrite in sensitized guinea pigs

The Effect of Crocus Sativus (Saffron) on the Respiratory System: Traditional and Experimental Evidence. Science of Spices and Culinary Herbs-Latest Laboratory

Antiinflammatory and immunomodulatory effects of saffron and its derivatives

The effect of Crocus sativus extract on human lymphocytes' cytokines and T helper 2/T helper 1 balance

The effect of the extract of Crocus sativus and its constituent safranal, on lung pathology and lung inflammation of ovalbumin sensitized guinea-pigs

Herbal medicines in management and prevention of COVID-19

Safranal of Crocus sativus L. inhibits inducible nitric oxide synthase and attenuates asthma in a mouse model of asthma

The effect of the extract of Crocus sativus on tracheal responsiveness and plasma levels of IL-4, IFN-γ, total NO and nitrite in ovalbumin sensitized Guinea-pigs

Human immunopathogenesis of severe acute respiratory syndrome (SARS)

Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19

A modified, economic, sensitive method for measuring total antioxidant capacities of human plasma and natural compounds using Indian saffron (Crocus sativus)

Crocus sativus, Serenoa repens and Pinus massoniana extracts modulate inflammatory response in isolated rat prostate challenged with LPS

Sixty-day outcomes among patients hospitalized with COVID-19

The impact of saffron administration on atherosclerosis development in an experimental animal model

COVID-19 Stats -Realtime coronavirus statistics with charts

Origin and evolution of pathogenic coronaviruses

Saffron suppresses oxidative stress in DMBA-induced skin carcinoma: A histopathological study

New insights into the biological properties of Crocus sativus L.: chemical modifications, human monoamine oxidases inhibition and molecular modeling studies

The effect of crocetin on hemorrhagic shock in rats

Effects of long-term treatment of colon adenocarcinoma with crocin, a carotenoid from saffron (Crocus sativus L.): an experimental study in the rat

Immunity against COVID-19: Potential role of Ayush Kwath

Crocus sativus L. versus citalopram in the treatment of major depressive disorder with anxious distress: a double-blind, controlled clinical trial

Effect of ethanol extract of saffron (Crocus sativus L.) on the inhibition of experimental autoimmune encephalomyelitis in C57bl/6 mice

The extract of Crocus sativus and its constituent safranal, affect serum levels of endothelin and total protein in sensitized guinea pigs

Crocetin from saffron: an active component of an ancient spice

An overview on saffron, phytochemicals, and medicinal properties

Preventive effect of crocin of Crocus sativus on hemodynamic, biochemical, histopathological and ultrastuctural alterations in isoproterenol-induced cardiotoxicity in rats

Management of postacute COVID-19 in primary care

Saffron (Crocus sativus) aqueous extract and its constituent crocin reduces stress-induced anorexia in mice

Identification of immunodominant epitopes on the membrane protein of the severe acute respiratory syndrome-associated coronavirus

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Evaluation of the antitussive effect of stigma and petals of saffron (Crocus sativus) and its components, safranal and crocin in guinea pigs

Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice

Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice

Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats

Insights from nanomedicine into chloroquineefcacy against COVID-19

Clinical features of patients infected with 2019 novel coronavirus in

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Husaini AM (2010) Foreword. In: Husaini (Ed.) Saffron, Global Science Books

Immunomodulatory effects of saffron: a randomized double-blind placebo-controlled clinical trial

PubChem 2019 update: improved access to chemical data

Investigation on penetration of saffron components through lipid bilayer bound to spike protein of SARS-CoV-2 using steered molecular dynamics simulation

The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application

Precis de Phytotherapie

Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia

Novel and known constituents from Buddleja species and their activity against leukocyte eicosanoid generation

Potential healthy effects of saffron spice (Crocus sativus L. stigmas) consumption

Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying anti-depressant mechanisms of action

Hydroalcoholic extract of Crocus sativus effects on bronchial inflammatory cells in ovalbumin sensitized rats

A randomized, double-blind, placebo-controlled study of safety of the adjunctive saffron on J o u r n a l P r e -p r o o f sexual dysfunction induced by a selective serotonin reuptake inhibitor

Saffron: A multitask neuroprotective agent for retinal degenerative diseases

Anti-diabetic and anti-hypertensive potential of sprouted and solid-state bioprocessed soybean

Safety and toxicity of saffron

Extrapyramidal side effects and increased serum prolactin following fluoxetine, a new anti-depressant

Available saffron formulations and product patents

Smooth muscle relaxant activity of Crocus sativus (saffron) and its constituents: possible mechanisms

The Effects of Saffron (Crocus sativus) and its Constituents on Immune System: Experimental and Clinical Evidence

Membrane associated antitumor effects of crocine-, ginsenoside-and cannabinoid derivates

Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia

Crocin acting as a neuroprotective agent against methamphetamine-induced neurodegeneration via CREB-BDNF signaling pathway

Antitumour activity of saffron (Crocus sativus)

Post-acute COVID-19 syndrome

Overview of Covid-19; its prevention and management in the light of Unani medicine

Hydroalcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild-tomoderate depression: a double-blind, randomized pilot trial

COVID-19: Current understanding of its pathophysiology, clinical presentation and treatment

Suppressive effects of Mimosa pudica (L.) constituents on the production of LPS-induced pro-inflammatory mediators

UCSF Chimera--a visualization system for exploratory research and analysis

Isolation and structure elucidation of carotenoid− glycosyl esters in gardenia fruits (gardenia jasminoidesellis) and saffron (crocus sativuslinne)

The effect of Crocus sativus L. and its constituents on memory: basic studies and clinical applications

Possible pharmacological and theoretical implications of X-ray structure of the tricyclic anti-depressant imipramine

Anticancer, antimutagenic and antioxidant potential of saffron: An overview of current awareness and future perspectives

Saffron-Immunity System

Dysregulation of immune response in patients with COVID-19 in Wuhan

SARS-CoV-2 and Coronavirus disease 2019: what we know so far

Saffron (Crocus sativus) and its active ingredients: role in the prevention and treatment of disease

The Effect of Water Soluble Carotenoids of Saffron on Cell

Saffron: a promising natural medicine in the treatment of metabolic syndrome

Safranal: from an aromatic natural product to a rewarding pharmacological agent

Saffron 2020 by Persavita: The Best Saffron Supplement for Macular Degeneration

Saffron in phytotherapy: pharmacology and clinical uses

The pyrin inflammasome in health and disease

Managing the long term effects of COVID-19: summary of NICE, SIGN, and RCGP rapid guideline

Immunostimulants: Types and functions

A randomized, double-blind, clinical trial comparing the efficacy and safety of Crocus sativus L. with fluoxetine for improving mild-to-moderate depression in post percutaneous coronary intervention patients

COVID-19 infection: the perspectives on immune responses

GalaxyDock2: protein-ligand docking using beta-complex and global optimization

Tu1284 protective effect of saffron in mouse colitis models through immune modulation

CD8(+) T cell-mediated injury in vivo progresses in the absence of eff ector T cells

Antiviral effects of saffron and its major ingredients

Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment

A double-blind, randomized, placebo-controlled trial of saffron stigma (Crocus sativus L.) in mothers suffering from mild-to-moderate postpartum depression

Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA

Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network-United States

ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis

Four in five patients with COVID-19 have persistent symptoms

Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase

Effect of stigmas of Crocus sativus L.(saffron) on cell mediated and humoral immunity

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

WHO Coronavirus Disease (COVID-19) Dashboard

The mercurial nature of neutrophils: still an enigma in ARDS?

Anti-asthma potential of crocin and its effect on MAPK signaling pathway in a murine model of allergic airway disease

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa

Increased expression ratio of Bcl-2/Bax is associated with crocin-mediated apoptosis in bovine aortic endothelial cells

Nabel, pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN

Suppression of NF-κB pathway by crocetin contributes to attenuation of lipopolysaccharide-induced acute lung injury in mice

Crocin has antiinflammatory and protective effects in ischemia-reperfusion induced renal injuries

Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan

COVID-19 pathophysiology: A review

Immunoregulatory and anti-inflammatory properties of Crocus sativus (Saffron) and its main active constituents: A review

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients

Virus-encoded proteinases and proteolytic processing in the Nidovirales