Benefit of Nigella sativa for Chronic Obstructive Pulmonary Disease Patients: A Narrative Review

Introduction: Chronic obstructive pulmonary disease ( COPD) is a prevalent respiratory disease that has a significant global impact. Unfortunately, current treatments and prevention remain insufficient. Nigella sativa (NS) has been traditionally used as an anti-inflammatory, antioxidant, and immunomodulatory agent, which can be helpful in the treatment of COPD, through its essential component thymoquinone. This review examined the potential benefits of NS for COPD patients as a possible treatment option. Methods: The literature investigation was conducted by searching relevant articles on Google Scholar and NCBI using the keywords "black seed", “black cumin”, " Nigella sativa", "thymoquinone", "carvacrol", and "COPD". The results from five identified studies were then summarized. Results: This review reveals that NS offers benefits to individuals with COPD by reducing inflammation and oxidative stress, thereby leading to improved pulmonary function tests (PFTs). However, it is important to note that the majority of experiments have been conducted on animals, with only one involving humans, and these experiments have mostly been short-term. Additionally, since different studies have used various preparations of NS, determining the recommended dose is challenging. Unfortunately, the research does not provide any insights into the potential long-term effects of these treatments or the possible adverse effects of the medications used. Conclusion: Studies on the benefits of NS as an anti-inflammatory and antioxidant for COPD adjuvant therapy show promising results, but more research is needed to confirm the findings with larger and more well-designed studies to determine the appropriate doses and long-term effects.


INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a common disease that can be prevented, treated, and characterized by persistent respiratory symptoms and airflow limitation due to abnormalities in the airways and/or alveoli caused by prolonged exposure to hazardous particles or gases. 1 It ranks as the third major cause of mortality worldwide and has a significant impact on morbidity and caused 3.23 million deaths in 2019, with an estimated 10% of individuals over 40 years old affected. 2,3moking is one of the primary known causes of COPD, and mounting evidence points to the innate immune system having a role in the disease progression. 4However, the pathophysiology of COPD is very complex, involving environmental factors, such as diet, allergies, and air pollution, as well as pathological mechanisms, such as oxidative stress, recruitment and activation of inflammatory cells, such as neutrophils, macrophages, and lymphocytes, inflammatory mediators and cytokine release, such as IL-1, IL-6, IL-8, TNF-α, and TGF-β, cell repair disruptions, such as apoptosis, necrosis, necrosis, and an imbalance of proteases/antiproteases, leading to tissue inflammation, airway damage and/or alveolar tissue and fibrosis, ultimately leading to the development of COPD. 5 The current treatment of COPD includes bronchodilators, anti-inflammatories, theophylline, and phosphodiesterase-4 (PDE4) inhibitors, which can be used as monotherapy or in combination.Preventive medicines that lower lung inflammation and relievers that decrease airway blockage are two medication types frequently used. 1 Despite the availability of various treatments for COPD, effective prevention and treatment for this disease remains inadequate. 6s prospective novel medicines, several studies have examined alternative remedies such as plant-based pharmaceuticals.One study examined the influence of herbal administration on patients with COPD or asthma and discovered a substantial decrease in IL-13 levels (a biomarker of obstructive airway disease and the primary mediator of inflammation in both diseases).This aids in the prevention of airway hyperresponsiveness, respiratory eosinophilia, and mucus secretion. 7A further systematic review also found that herbal medicines were effective in improving forced expiratory volume in one second (FEV1), FEV1 (%), 6-minute walk distance, and forced vital capacity (FVC), as well as improving several pulmonary functions, complaints, and quality of life in COPD patients, even though the evidence is still mainly of low quality.The precise mechanisms and implications must be thoroughly investigated. 8Thus, examination of more herbs is really important, including the use of Nigella sativa (NS).Numerous studies have demonstrated the therapeutic properties of extracts from NS, which have been utilized for centuries as food additives and herbal remedies in ancient cultures to treat a variety of ailments. 9S, commonly known as black cumin or habbatussauda, is a member of the Ranunculaceae family.This plant has been widely used in traditional medicine across the globe, particularly in Europe, the Middle East, and South Asia, due to its natural therapeutic properties in treating a variety of diseases and conditions. 102][13] Thymoquinone (TQ), the principal constituent of NS, has exhibited promising potential in the NS treatment of respiratory conditions like asthma and COPD by suppressing the release of inflammatory mediators and regulating the immune system via antioxidant enzymes. 14NS extract has also been found to have beneficial effects on Alzheimer's, ischemic stroke, traumatic brain injury, anxiety and depression, epilepsy, schizophrenia, diabetes, hypertension, hepatotoxicity, fertility, anti-cancer effects, acne vulgaris, vitiligo, rheumatoid arthritis, and wound healing. 9This review provides a contemporary summary of the impact of NS and its constituents on COPD.

SEARCH METHODS
This review used articles in online literature using Google Scholar and NCBI that illustrate the role of black cumin in COPD.The keywords used were: "black seed", "black cumin", "Nigella sativa", "thymoquinone", "carvacrol", and "COPD".Five relevant studies were found and summarized.

RESULTS
Studies conducted on both animals and humans have revealed that NS, commonly referred to as black seed or black cumin and classified under the Ranunculaceae family, possesses diverse therapeutic and medicinal properties.2][13] Lung inflammation is a characteristic feature of obstructive respiratory conditions such as asthma and COPD.Inflammatory gene expression is triggered by oxidative stress in addition to infections, contributing to respiratory diseases like COPD and asthma. 15It is summarized in Table 1.
Black cumin, particularly its essential oil, contains compounds such as TQ, carvacrol, thymohydroquinone, thymol, nigellidine, nigellicine, and α-hederin, which account for the bulk of its pharmacological effects and therapeutic advantages. 16he biological activity of NS is due to TQ, one of the most potent substances in the plant.TQ accounts for 54% of volatile black seed oil (BSO) and has been shown in tests to have anti-oxidant, anti-inflammatory, and anti-tumor properties.The biological properties of black seed are also attributable to various other components present in it, including proteins, carbohydrates, minerals, vitamins, fixed oil, volatile oil, saponins, alkaloids, and other compounds. 17Q is an anti-inflammatory in COPD and acts by targeting several key mechanisms.It weakens prostaglandins and leukotrienes, regulates cell proliferation and inflammation through the NF-κB pathway, regulates TNF-α transcription, and reduces tissue damage through inducing NF-κB binding.TQ also blocks NF-κB activity in serum by inhibiting IKK enzyme activation and inducing the binding of IκB, p50, and p65, preventing the translocation of NFk-ß to the nucleus and inhibiting cytokine expression, including IL-8 (also known as CXCL8).][20] Systemic production of TNF-α, a powerful proinflammatory cytokine, is largely dependent on activated macrophages.The expression and release of various proinflammatory mediators that cause tissue damage and remodeling are sustained and promoted by a cytokine believed to be a crucial player in the development of COPD.TNF-α levels have been found to be elevated in COPD patients, suggesting systemic inflammation. 13ultiple cell types in the lungs, including macrophages, interstitial fibroblasts, epithelium cells, and other inflammatory cells, are responsible for IL-6 production.Elevated levels of IL-6 were discovered in the induced sputum of people with COPD, which led to the hypothesis that IL-6 played a role in the disease progression.Airflow limitation in COPD patients was found to worsen with increasing IL-6 levels, especially during the acute exacerbation period.3][24] 25 The study used a prospective randomized controlled double-blind clinical trial design and found that the BSO group had significant improvements in various markers of COPD compared to the control group receiving standard medication only. 25he advantages of the study involve utilizing a randomized controlled trial design and assessing different markers of COPD.Limitations of the study include its small sample size, limited duration of followup, and the fact that the BSO group was not compared to a group receiving the standard medication only.Despite these limitations, the results of the study suggest that BSO supplementation may be beneficial for COPD patients and warrant further investigation.
Yetkin, et al. (2020) intended to investigate the potential preventative and therapeutic effects of TQ on cigarette smoke-induced damage of lung in rats. 26The study was conducted on 50 adult male rats, with 30 of them being exposed to cigarette smoke for 3 months.The study design involved dividing the rats into five groups with different treatments and control groups.The protective and curative effects of TQ were observed by administering TQ (2 mg/kg) via intraperitoneal injection to some of the rats for different periods of time.The study showed that the level of IL-6 decreased significantly in the rats that were treated with TQ during the last 21 days of the study.Cigarette smoke exposure was associated with elevated amounts of both serum and IL-1ß and IL-8 compared to the control group.Although not statistically significant, the study indicated that TQ may have an anti-inflammatory effect by reducing the levels of IL-8. 26The study design was appropriate, as it included control groups and used statistical methods for data analysis.Given the limitation of the study, 50 rat sample size may not be sufficient, and the data should be interpreted with caution.
Another study was conducted on stable COPD patients under outpatient control at the Pulmonology Clinic of Dr. Moewardi General Hospital, Surakarta, and Dr. Soehadi Prijonegoro General Hospital, Sragen, Indonesia. 27The study involved 40 patients diagnosed with stable COPD who were separated into two groups, a control group (20 patients) and a treatment group (20  patients).The treatment group received TQ oil capsules in addition to standard COPD therapy for a duration of 30 days, whereas the control group received only the standard therapy.IL-8, spirometry, and at the onset and conclusion of the study, COPD assessment test (CAT) questionnaire scores were noted, and statistical tests were conducted to assess the distinctions in IL-8 levels between the two groups.As shown by the data, IL-8 levels rose significantly (p = 0.004) in the control group but did not vary significantly (p = 0.052) in the treatment group.The anti-inflammatory effects of TQ in COPD patients are a result of its ability to modulate cell growth and inflammation by inhibiting the NF-kB pathway. 27While the results suggest the potential for TQ as an anti-inflammatory in stable COPD patients, the limitations of the study must be considered, such as the small sample size, unclear randomization and blinding, lack of baseline comparability, short treatment duration, and the potential for confounding variables.Further research is needed to confirm these findings.
An earlier study by Mahtaj, et al. (2015) was conducted in Iran to investigate the effects of cigarette smoke on guinea pigs and evaluate the potential therapeutic benefits of dexamethasone and carvacrol. 28he study involved the random allocation of 33 guinea pigs into 6 groups, which were then subjected to cigarette fumes for three months.The baseline group received only ambient air and drinking water, whereas the COPD group received only cigarette smoke.The COPD + dexamethasone group received 80 drinking water containing dexamethasone, and the COPD + carvacrol groups received drinking water containing different doses of carvacrol.A greater mean IL-8 level was observed in the COPD group compared to the control group.Serum IL-8 levels were reduced in the dexamethasone and carvacrol-treated COPD groups compared to those in the untreated COPD group.The study also found that the COPD group had a significant increase in the number of total white blood cells (WBC) and eosinophils compared to the control group.This increase was reduced in the COPD groups that were given higher doses of carvacrol and dexamethasone. 28he study appears to have a good experimental design with proper randomization, control, and treatments.Despite the interesting findings, the sample size of the study was limited, with only 5-6 animals in each group.The outcomes therefore may not be applicable to broader populations.Additionally, the study does not offer any insight into the probable long-term consequences of the treatments or the potential adverse effects of the medications administered.Further research is needed to validate these findings.
Lipopolysaccharide (LPS) induces lung injury via multiple inflammatory mechanisms. 29LPS increased the production of inflammatory cytokines via NF-κB cascade signaling pathways. 30The study by Mokhtari-Zaer, et al. (2020) was conducted in Iran to examine how NS impacts lung inflammation and oxidative stress caused by LPS in rats. 29Different sets of male rats were analyzed, control, LPS-administered, and LPS-administered with NS at 3 different doses.LPS was administered daily for 14 days, and NS treatment started 2 days prior to LPS administration and continued during the LPS treatment.To compare the groups, a one-way analysis of variance and Tukey multiple comparison tests were used.The outcomes revealed that administering LPS significantly elevated the levels of INF-γ, IL-4, TGF-ß1, and PGE2 in the blood and bronchoalveolar lavage fluid of the male rats in comparison to the control group.Nevertheless, administering NS at doses of 100, 200, and 400 mg/kg considerably decreased the levels of INF-γ, TGF-ß1, and PGE2, while progressively increasing IL-4 levels. 29

SUMMARY
Based on the examination, NS may help patients with COPD as adjuvant therapy due to its effect on reducing inflammation, limiting oxidative stress, and enhancing pulmonary function.The essential components of NS that play a role in anti-inflammatory and antioxidant properties are TQ and carvacrol.However, the evidence is still limited, since the included studies only have small sample sizes, short treatment duration, unclear randomization and blinding, lack of baseline comparability, and the potential for confounding variables.The recommended dose of NS for COPD treatment remains unclear.Therefore, the results should be interpreted with caution and further well-designed and larger studies to confirm these findings and to determine the appropriate doses and long-term effects of these natural supplements.In conclusion, more research is needed to determine the efficacy and safety of these natural supplements in treating COPD and lung damage.

Table 1 .
Summary of studies evaluating NS impact to treat COPD Compared to the control group, the group exposed to CS showed increased levels of IL-1β and IL-8 • TQ's anti-inflammatory effects were shown by the fact that IL-8 levels were lower in the treatment group compared to the control group • All groups exposed to CS exhibited a higher AI than the control group • The AI score was lower in the group that had been given TQ for the previous 21 days than in the other CS groups • In comparison to the other CS groups, the group that received TQ daily displayed an increase in the AI • When administered at suitable doses, TQ has curative effects on CS-induced inflammation and may prevent apoptosis Azzawi, et al. (2020) in Egypt set out to see what effect supplementing with BSO would have on PFTs, inflammation, and oxidant-antioxidant indicators in people with COPD.