Ethnobotanical Uses and Pharmacological Activities of Moroccan Ephedra Species.

Ephedra species are among the most popular herbs used in traditional medicine for a long time. The ancient Chinese medical book "Treatise on Febrile Diseases" refers to the classic traditional Chinese medicine prescription Ge Gen decoction, which consists of seven herbs, including an Ephedra species. Ephedra species are utilized all over the world to treat symptoms of the common cold and coughs, and to combat major human diseases, such as asthma, cancers, diabetes, cardiovascular and digestive disorders, and microbial infections. This study aimed at identifying specific Ephedra species used traditionally in Morocco for therapeutic purposes. The plant parts, their preparation process, and the treated pathologies were identified and analyzed. The results revealed five ethnobotanically important species of Ephedra: Ephedra alata Decne, Ephedra altissima Desf., Ephedra distachya L., Ephedra fragilis Desf., and Ephedra nebrodensis Tineo. These species are used traditionally in Morocco for treating people with diabetes, cancer, rheumatism, cold and asthma, hypertension, influenza virus infection, and respiratory ailments. In addition, they are occasionally used as calefacient agents, to regulate weight, or for capillary care. Few studies have underlined the antibacterial and antioxidant activities of some of these Moroccan Ephedra species, but little information is available regarding the natural products at the origin of the bioactivities. Further phytochemical investigations and clinical data are encouraged to better support the use of these plants.

In vitro anti-severe acute respiratory syndrome coronavirus 2 effect of Ephedra przewalskii Stapf extract.

ETHNOPHARMACOLOGICAL RELEVANCE: The terrestrial stems of Ephedra (Ephedra spp.; including Ephedra sinica Stapf and Ephedra przewalskii Stapf) extracts are used in traditional medicines in East Asia. In Japan, the Kampo formula containing E. sinica extract is prescribed for the treatment of the common cold, influenza virus infections, and mild symptoms of coronavirus disease 2019 (COVID-19). Although ephedrine alkaloids in E. sinica exert antitussive effects, they may have side effects associated with the sympathetic nervous system. E. przewalskii extract, a drug used in traditional Uyghur and Mongolian medicine, is considered to be free of ephedrine alkaloids and is a promising candidate for the treatment of infectious diseases. However, its use is currently limited because evidence of its antiviral efficacy remains inconclusive. AIM OF THE STUDY: We compared the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) effects of E. przewalskii and E. sinica extracts in vitro. Additionally, we examined the differences in their antiviral effects against different SARS-CoV-2 strains. MATERIALS AND METHODS: VeroE6/TMPRSS2 cells were infected with SARS-CoV-2 (Conventional, Delta, and Omicron strains-BA.1, BA.2, BA.4, and BA.5), and lysates prepared from each herbal extract were added. The infectious titer was determined using the 50% tissue culture infectious dose (TCID50) method; in turn, the half-maximal inhibitory concentration (IC50) was calculated for each extract to compare the antiviral efficacy of E. sinica and E. przewalskii extracts. Further, the extracts were compared with remdesivir for their antiviral efficacy against the conventional viral strain. To verify the effect of the inactivation of virus particles, these extracts were added to each SARS-CoV-2 strain, and the infectious titers were determined using the TCID50 method. RESULTS: The antiviral efficacy (i.e., IC50) of the E. przewalskii extract against each SARS-CoV-2 strain was 2.7-10.8-fold greater than that of the E. sinica extract. The antiviral efficacy of the E. przewalskii extract against conventional viral strains was compared with that of remdesivir, which was 1/27.6 of remdesivir's efficacy. The E. sinica extract showed minimal inactivation of virus particles of each strain, whereas the E. przewalskii extract resulted in substantial viral inactivation. CONCLUSIONS: The E. przewalskii extract showed higher antiviral activity against SARS-CoV-2 than the E. sinica extract. Overall, our study suggests that E. przewalskii extract can be used for the treatment of viral infections, including COVID-19.

Alanda (Ephedra foeminea) nanoparticles as a modulator of genomic DNA degradation in mice: new inspiration for treating Ehrlich solid tumour-induced kidney and liver toxicity.

OBJECTIVE: The limitations faced by conventional drug delivery systems are being overcome through the use of rapidly evolving cancer nanotherapeutics. Determining the manner in which the Ehrlich solid tumor (EST) is impacted by the new bioactive Alanda-loaded flax seed gum nanoparticles (Alanda NPs) functioning as an anti-carcinogenic agent represents the research objective of this paper. MATERIALS AND METHODS: Identification of the functional groups, surface morphology, particle size, and zeta potential were among the characterizations and preparations made for the prepared nanoparticles. A Control group, a Flax Seed Gum group, a raw Alanda group, an Alanda NPs group, an EST group, and an induced EST treated with Alanda NPs group comprised the six groups respectively which the 60 female mice were separated into in this in vivo study. RESULTS: Toxicity assessments for kidneys and liver were performed alongside the detection of total genomic DNA degradation. The zeta potential and the particle sizes for Alanda NPs were -25.60±0.38 mv and 40±0.28 nm, respectively, where the latter demonstrated a monodisperse spherical shape, per the findings. The use of Alanda NPs to treat EST was found to alle te the DNA damage, apoptosis, and renal and hepatic toxicity that EST induces. Additionally, the activation of oxidative stress and apoptosis causing the renal and hepatic toxicity induced by EST is counteracted by the scavenging of free radicals by the Alanda NPs. CONCLUSIONS: A high degree of safety for effective cancer treatment was displayed by the newly developed oral nanoparticles while also demonstrating strong potential in vivo.

Ephedrine and pseudoephedrine in Ephedra saxatilis on the vertical altitude gradient changed in southern Tibet Plateau, China.

Ephedra is one of the world's most important plants, used in medicine, plants and ecology. Most Ephedra grows in plain areas and is stable. But the plateau environment is special, with the change of altitude, the variety difference of plateau Ephedra saxatilis is very obvious. E. saxatilis metabolism on the Tibetan Plateau is not only affected by altitude, but also environmental conditions such as climate conditions and different soil components. However, the change mechanism of E. saxatilis alkaloids in special ecological environment is still unclear. Therefore, we analyzed the metabolic and altitude of E. saxatilis species in the Tibetan Plateau. Through the functional analysis of Kyoto Metabolism and Metabolomic Encyclopedia (KEGG), we can determine that the number of E. saxatilis metabolites decreases with the increase of altitude, and there are differences in metabolism among the three mountains. This was confirmed by univariate analysis of the top five metabolic pathways. Based on the analysis of soil and metabolomics, it was found that soil water content was also a factor affecting E. saxatilis metabolism. According to the difference of vertical height gradient, ephedrine and pseudephedrine showed the same change in vertical altitude under different mountains. Ephedrine increased as the altitude gradient increased, and pseudoephedrine decreased as the altitude gradient decreased. Our results provide valuable information for further study of metabolic mechanism and efficacy stability. It provides useful reference for the research of E. saxatilis planting in special area.

Inhibitory effect of Ephedra herba on human norovirus infection in human intestinal organoids.

Human norovirus (HuNoV) is a major cause of acute gastroenteritis and foodborne diseases worldwide with public health concern, yet no antiviral therapies have been developed. In this study, we aimed to screen crude drugs, which are components of Japanese traditional medicine, ''Kampo'' to see their effects on HuNoV infection using a reproducible HuNoV cultivation system, stem-cell derived human intestinal organoids/enteroids (HIOs). Among the 22 crude drugs tested, Ephedra herba significantly inhibited HuNoV infection in HIOs. A time-of-drug addition experiment suggested that this crude drug more preferentially targets post-entry step than entry step for the inhibition. To our knowledge, this is the first anti-HuNoV inhibitor screen targeting crude drugs, and Ephedra herba was identified as a novel inhibitor candidate that merits further study.

Predicting the comprehensive geospatial pattern of two ephedrine-type alkaloids for Ephedra sinica in Inner Mongolia.

Ephedra sinica Stapf. is a shrubby plant widely used in traditional Chinese medicine due to its high level of medicinal value, thus, it is in high demand. Ephedrine (E) and pseudoephedrine (PE) are key medicinal components and quality indicators for E. sinica. These two ephedrine-type alkaloids are basic elements that exert the medicinal effect of E. sinica. Recently, indiscriminate destruction and grassland desertification have caused the quantity and quality of these pharmacological plants to degenerate. Predicting potentially suitable habitat for high-quality E. sinica is essential for its future conservation and domestication. In this study, MaxEnt software was utilized to map suitable habitats for E. sinica in Inner Mongolia based on occurrence data and a set of variables related to climate, soil, topography and human impact. The model parametrization was optimized by evaluating alternative combinations of feature classes and values of the regularization multiplier. Second, a geospatial quality model was fitted to relate E and PE contents to the same environmental variables and to predict their spatial patterns across the study area. Outputs from the two models were finally coupled to map areas predicted to have both suitable conditions for E. sinica and high alkaloid content. Our results indicate that E. sinica with high-quality E content was mainly distributed in the Horqin, Ulan Butong and Wulanchabu grasslands. E. sinica with high-quality PE content was primarily found in the Ordos, Wulanchabu and Ulan Butong grasslands. This study provides scientific information for the protection and sustainable utilization of E. sinica. It can also help to control and prevent desertification in Inner Mongolia.

Ecological and pharmacognostical characteristics in Ephedra saxatilis in the Yarlung Zangbo River Valley of southeastern Tibetan Plateau, China.

In the Yarlung Zangbo River Valley of the southeastern Tibetan Plateau, China (29°07'49.5"N, 92°41'11.0"E, 3256 m above sea level), we found an Ephedra saxatilis community in the xeric steppe with shrubland vegetation habitat of the broad alluvial plain of the river with soil having relatively higher water-soluble cation (Ca2+, 8.62; K+, 1.94; Mg2+, 2.38 mmol/100 g dry soil weight) and nitrogen (NO3-, 21.78; NH4+, 1.82 mmol/100 g dry soil weight) content. The ranges of ephedrine and pseudoephedrine in 13 E. saxatilis samples were as follows: ephedrine, not detected-3.03 of dry weight (%DW) and pseudoephedrine, not detected-1.36%DW. The 13 E. saxatilis plants collected in the study area showed intraspecific variability of ephedrine and pseudoephedrine with 6 samples containing ephedrine and pseudoephedrine, 6 samples containing only ephedrine, and 1 sample containing only pseudoephedrine.

Comparative pharmacokinetic studies of Ephedra herba in common cold and nephrotic syndrome rat models.

Ephedra herba is a conventional Chinese medicine to treat cold, fever, asthma, edema, and lung diseases in the clinic. At present, most pharmacokinetic studies focus on the pharmacokinetic process of alkaloids in normal animals. However, the non-alkaloid components are also active. In addition, the pharmacokinetic studies under pathological state make more sense for clarifying the material basis of efficacy. In this study, a sensitive and rapid ultra-high-performance-tandem mass spectrometry method was developed and applied to determine nine bioactive components (ephedrine, pseudoephedrine, methylephedrine, (+)-catechin, epicatechin, vitexin, vicenin-2, cinnamic acid, and ferulic acid) in normal, common cold and nephrotic syndrome rats after the oral administration of Ephedra herba. Compared to the normal group, except for ferulic acid, the exposure levels of the other eight components were significantly increased and the plasma clearance clearly declined in common cold rats. Similarly, the exposure levels of seven components other than cinnamic acid and ferulic acid were also significantly augmented and the plasma clearance decreased significantly in nephrotic syndrome rats. In brief, the pathological conditions of the common cold and nephrotic syndrome could lead to alterations in the pharmacokinetics profiles of the nine components, which provide a reference for further exploration of the pharmacodynamics basis of Ephedra herba.

Ephedrae herba: A comprehensive review of its traditional uses, phytochemistry, pharmacology, and toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Ephedrae herba (called Mahuang in China) is the dried herbaceous stem of Ephedra sinica Stapf, Ephedra intermedia Schrenk et C. A. Mey., and Ephedra equisetina Bge. Ephedrae herba has a long history of use as an herb, and it was originally recorded in Sheng Nong's herbal classic. Ephedrae herba has also been widely used as both medicine and food. In the clinic, Ephedrae herba is commonly used for treating colds, bronchial asthma, nasal congestion, and other diseases. AIM OF REVIEW: This review aims to provide a systematic summary on the traditional use, chemical constituents, pharmacological effects, clinical applications, quality control, toxicology, and pharmacokinetics of Ephedrae herba to provide a theoretical basis for further reasonable development of Ephedrae herba in clinical practice and creation of new drugs. MATERIALS AND METHODS: Information on Ephedrae herba was gathered from various sources, including the scientific databases including CNKI, PubMed, SciFinder and ScienceDirect, classical books on traditional Chinese herbal medicine, Ph.D. and M.Sc. dissertations; Baidu Scholar; and from different professional websites. RESULTS: Ephedrae herba is distributed in regions of China and other areas. Ephedra and its compound preparations can be used for colds, bronchial asthma, nasal congestion and other diseases. Approximately 281 chemical constituents have been isolated from Ephedrae herba, including alkaloids, flavonoids, tannins, polysaccharides, volatile oils, organic acids, and other compounds. Among these constituents, alkaloids and volatile oils are the most abundant and represent the major bioactive constituents. Ephedrae herba possesses multiple pharmacological activities, including diuretic effect, anti-allergic effect, blood pressure regulatory, anti-inflammatory effect, anti-oxidation effect and anti-viral effects. Ephedrine hydrochloride and pseudoephedrine hydrochloride are generally selected as indicators for the quantitative determination of Ephedrae herba. The maximum dosage of Ephedrae herba should not exceed 10 g. If overused, adverse reactions such as palpitations, sweating, irritability and insomnia will occur. CONCLUSIONS: Ephedrae herba is an ancient herbal medicine with a broad spectrum of pharmacological activities that has been used for thousands of years in China. It is one of the most commonly used herbal components of the TCM formulas. Hydrochloride and pseudoephedrine are the major bioactive constituents. However, there is a need to further understand the mechanisms of active components of Ephedrae herba. Future studies should perform an in-depth analyses of the pharmacokinetics and mechanisms of toxicity of Ephedrae herba. Quality standards should be developed to correspond to the various application methods to ensure the efficacy of drugs in actual treatment.

Evaluation of rooting characteristics of Ephedra cuttings by anatomy and promising strain selection based on rooting characteristics and alkaloid content.

The differences in rooting characteristics of cuttings prepared from E. sinica strains were investigated and found that cuttings prepared from strains with high rooting characteristics showed approximately 90% of the cuttings were rooted, whereas cuttings prepared from low rooting characteristics did not root. To understand the reason for this substantial difference, the anatomy of nodes was examined and found that adventitious roots were generated from the cortex and parenchyma in pith. Calculations of the correlation coefficients between the rooting rate and the value of anatomy indicated that the rooting rate was positively correlated with the parenchyma in pith in the node. On the basis of the positive correlation, it is possible to estimate the rooting characteristics of new strains without having to prepare cuttings. Next, we conducted a screening for E. sinica strains on the basis of total alkaloids content [ephedrine (E) + pseudoephedrine (PE)] and selected strains having no less than 0.7% total alkaloids content as defined by the Japanese Pharmacopoeia 18th edition. Strains having characteristic E or PE content were uncovered: E-rich strains had 100% E content and PE-rich strains had 99% PE content. We were able to select E. sinica strains on the basis of two factors: high rooting rate of cuttings and high or characteristic alkaloid content. These strains are valuable for breeding.

Ephedrae Herba: A Review of Its Phytochemistry, Pharmacology, Clinical Application, and Alkaloid Toxicity.

Ephedrae Herba (Ephedra), known as "MaHuang" in China, is the dried straw stem that is associated with the lung and urinary bladder meridians. At present, more than 60 species of Ephedra plants have been identified, which contain more than 100 compounds, including alkaloids, flavonoids, tannins, sugars, and organic phenolic acids. This herb has long been used to treat asthma, liver disease, skin disease, and other diseases, and has shown unique efficacy in the treatment of COVID-19 infection. Because alkaloids are the main components causing toxicity, the safety of Ephedra must be considered. However, the nonalkaloid components of Ephedra can be effectively used to replace ephedrine extracts to treat some diseases, and reasonable use can ensure the safety of Ephedra. We reviewed the phytochemistry, pharmacology, clinical application, and alkaloid toxicity of Ephedra, and describe prospects for its future development to facilitate the development of Ephedra.

Phytochemical Screening, Antioxidant Potential, and LC-ESI-MS Profiling of Ephedra alata and Ephedra altissima Seeds Naturally Growing in Tunisia.

Most Ephedra species are adapted to arid and desert conditions and are widely used in folk medicine to treat several disorders. The design of the current study was to determine the functional properties of seeds of two Ephedra species (E. alata and E. altissima) naturally growing in Tunisian arid zones by evaluating their mineral contents and bioactive compounds. The flame atomic absorption spectrometry revealed that seeds contained remarkable amounts of sodium (Na), potassium (K), calcium (Ca), magnesium (Mg), copper (Cu), zinc (Zn), and iron (Fe). The colorimetric investigation revealed high total polyphenol, flavonoid, and condensed tannin contents. Furthermore, by utilizing high-performance liquid chromatography-electrospray ionization-mass spectrometry method (HPLC-ESI/MS), a total of 11 phenolics were identified and quantified including 7 flavonoid compounds and 4 phenolic acids that were mostly predominated by gallic acid and quercetrin. Results so far have been very encouraging and proved that Ephedra seeds are a valuable source of natural bioactive compounds and minerals which could potentially be used for industrial and pharmaceutical purposes.

Seasonal variation of alkaloids and polyphenol in Ephedra sinica cultivated in Japan and controlling factors.

We investigated the seasonal variation of alkaloids (ephedrine and pseudoephedrine), total polyphenol, and sugar contents in Ephedra sinica cultivated in Japan and elucidated the controlling factors for the variation. In 2018, alkaloids and polyphenol contents increased dramatically from May to July, decreased to their lowest in October, and slightly increased again in November. The reduction of alkaloids and polyphenol contents in the autumn may be affected by precipitation in summer. In 2020, alkaloids and polyphenol contents started to decrease in late July when rainfall was abundant from July to August. In contrast, sucrose and starch contents continued to increase until September and remained high until October. Vascular bundles and fiber developed, and herbal stem weight increased from August to October. Alkaloids and total polyphenol contents tended to increase in November. At the same time, starch and sucrose contents decreased dramatically, whereas glucose and fructose contents increased. Sugar content decreased from October and was lowest in November. The seasonal variation of alkaloids and total polyphenol contents exhibited a contrasting tendency to the seasonal variation of sugar content and tissue development. The seasonal variation of alkaloids and total polyphenol contents was caused by the seasonal variation of sugar content and tissue development. In addition, it is suggested that anatomy may be used for alkaloids content estimation in Ephedra plants.

Overlooked switch from transient sedation to sustained excitement in the Biphasic effects of Ephedra Herb extract administered orally to mice.

ETHNOPHARMACOLOGICAL RELEVANCE: In our previous study, we reported that Ephedra Herb extract (EHE) increased the locomotor activity of mice in the open-field test and reduced the immobility time in the forced swim test. Ephedrine alkaloids (EAs) are thought to be responsible for the adverse effects of Ephedra Herb. However, there are no reports to verify that the adverse effects of Ephedra Herb are caused by the amount of EAs in the herb. Therefore, we investigated whether these adverse effects of EHE are caused by the amounts of ephedrine (Eph) and pseudoephedrine (Pse) in the herbal extract. In a preliminary study of the time course analysis of the open field test, we newly observed that EHE evoked switching from transient sedation to sustained excitement. AIM OF THE STUDY: We aimed to confirm whether EHE evokes switching from transient sedation to sustained excitement, investigate whether these actions of EHE are caused by the amount of ephedrine (Eph) and pseudoephedrine (Pse) in the herbal extract, and clarify the molecular mechanism of the transient sedative effect. MATERIALS AND METHODS: The locomotor activity of mice was tested using the open-field test. The immobility times were measured using a forced swim test, and the motor dysfunction in mice was tested using the rotarod test. RESULTS: EHE, Eph, and Pse induced transient motionlessness between 0 and 15 min after oral administration, however, they did not induce depression-like behavior and motor dysfunction in mice, suggesting that the motionlessness induced by EHE, Eph, or Pse resulted from sedation. The α2a adrenoceptor inhibitor, atipamezole, decreased their sedative effects. Thus, immediately after EHE administration, the transient sedative effect is mediated through the activation of the α2a adrenoreceptor by Eph and Pse. EHE and Eph increased total locomotor activity for 15-120 min after oral administration; however, Pse had no effect. Therefore, the slow-onset and sustained excitatory effects of EHE are mediated by Eph. CONCLUSIONS: We discovered for the first time that EHE evokes diphasic action by switching from transient sedation to sustained excitement. The transient sedation was evoked by the Eph and Pse in the herbal extract via activation of the α2a adrenoceptor and the sustained excitement was caused by the Eph in the herbal extract.

Bio-Guided Assay of Ephedra foeminea Forssk Extracts and Anticancer Activities: In Vivo, In Vitro, and In Silico Evaluations.

Ephedra is one of the oldest known medicinal plants and the largest genera of the Ephedraceae family. In vivo antitumor evaluation of Ephedra foeminea revealed that ethyl acetate (EtOAc) was the most bioactive fraction. Bio-guided fractionation of EtOAc fraction afforded nine compounds isolated for the first time from the plant species. Macrocyclic spermine alkaloids (1,9), proanthocyanidins (2,4,5), quinoline alkaloids (7,8), phenolic (3), and nucleoside (6) were identified and elucidated by spectroscopic analyses including 1D and 2D NMR, ESI-MS-MS spectrometry. The tested compounds exhibited moderate anticancer activity, except for the kynurenic acid derivative (6-mKYNA) which showed significant cytotoxicity and remarkable inhibition of CA-19.9 and CA-125 tumor biomarkers. In-silico study was conducted to determine the anti-proliferative mechanism of 6-mKYNA by using the CK2 enzyme active site. Moreover, the ADME computational study suggested that 6-mKYNA is an effective candidate with a promising pharmacokinetic profile and therapeutic potential against various types of cancer.

[Mechanism of "Ephedrae Herba-Descurainiae Semen Lepidii Semen" combination in treatment of bronchial asthma based on network pharmacology and experimental verification].

This study aims to investigate mechanism of "Ephedrae Herba-Descurainiae Semen Lepidii Semen" combination(MT) in the treatment of bronchial asthma based on network pharmacology and in vivo experiment, which is expected to lay a theoretical basis for clinical application of the combination. First, the potential targets of MT in the treatment of bronchial asthma were predicted based on network pharmacology, and the "Chinese medicine-active component-target-pathway-disease" network was constructed, followed by Gene Oncology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment of the potential targets. Molecular docking was used to determine the binding activity of key candidate active components to hub genes. Ovalbumin(OVA, intraperitoneal injection for sensitization and nebulization for excitation) was used to induce bronchial asthma in rats. Rats were classified into control group(CON), model group(M), dexamethasone group(DEX, 0.075 mg·kg~(-1)), and MT(1∶1.5) group. Hematoxylin and eosin(HE), Masson, and periodic acid-Schiff(PAS) staining were performed to observe the effect of MT on pathological changes of lungs and trachea and goblet cell proliferation in asthma rats. The levels of transforming growth factor(TGF)-ß1, interleukin(IL)6, and IL10 in rat serum were detected by enzyme-linked immunosorbent assay(ELISA), and the mRNA and protein levels of mitogen-activated protein kinase 8(MAPK8), cyclin D1(CCND1), IL6, epidermal growth factor receptor(EGFR), phosphatidylinositol 3-kinase(PI3 K), and protein kinase B(Akt) by qRT-PCR and Western blot. Network pharmacology predicted that MAPK8, CCND1, IL6, and EGFR were the potential targets of MT in the treatment of asthma, which may be related to PI3 K/Akt signaling pathway. Quercetin and ß-sitosterol in MT acted on a lot of targets related to asthma, and molecular docking results showed that quercetin and ß-sitosterol had strong binding activity to MAPK, PI3 K, and Akt. In vivo experiment showed that MT could effectively alleviate the symptoms of OVA-induced asthma rats, improve the pathological changes of lung tissue, reduce the production of goblet cells, inhibit the inflammatory response of asthma rats, suppress the expression of MAPK8, CCND1, IL6, and EGFR, and regulate the PI3 K/Akt signaling pathway. Therefore, MT may relieve the symptoms and inhibit inflammation of asthma rats by regulating the PI3 K/Akt signaling pathway, and quercetin and ß-sitosterol are the candidate active components.

[Mahuang (herbaceous stem of Ephedra spp.): chemistry, pharmacodynamics, and pharmacokinetics].

The Chinese medicinal herb Mahuang is herbaceous stem of Ephedra sinica, E. intermedia, or E. equisetina(Family, Ephedraceae). In China, Mahuang has been used, all the way over a millennium, as a key component herb of many herbal medicines for management of epidemics of acute respiratory illness and is also used in officially recommended herbal medicines for COVID-19. Mahuang is the first-line medicinal herb for cold and wheezing and also an effective diuretic herb for edema. However, Mahuang can also exert significant adverse effects. The key to safety and effectiveness is rational and precise use of the herb. In this review article, we comprehensively summarize chemical composition of Mahuang and associated differences in pharmacognosy, pharmacodynamics and pharmacokinetics of Mahuang compounds, along with the adverse effects of Mahuang compounds and products. Based on full understanding of how Mahuang is used in Chinese traditional medicine, systematic research on Mahuang in line with contemporary standards of pharmaceutical sciences will facilitate promoting Chinese herbal medicines to become more efficient in management of epidemic illnesses, such as COVID-19. To this end, we recommend research on Mahuang of two aspects, i.e., pharmacological investigation for its multicompound-involved therapeutic effects and toxicological investigation for clinical manifestation of the adverse effects, chemicals responsible for the adverse effects, and conditions for safe use of the herb and the herb-containing medicines.

Potential Molecular Mechanisms of Ephedra Herb in the Treatment of Nephrotic Syndrome Based on Network Pharmacology and Molecular Docking.

Objective: To explore the possible mechanisms of Ephedra herb (EH) in the treatment of nephrotic syndrome (NS) by using network pharmacology and molecular docking in this study. Methods: Active ingredients and related targets of EH were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and the gene names corresponding to the proteins were found through the UniProt database. Then, target genes related to NS were screened out from GeneCards, PharmGKB, and OMIM databases. Next, the intersection targets were obtained successfully through Venn diagram, which were also seen as key target genes of EH and NS. Cytoscape 3.9.0 software was used to construct the effective "active ingredient-target" network diagram, and "drug-ingredient-target-disease (D-I-T-D)" network diagram. After that, the STRING database was used to construct a protein-protein interaction (PPI) network. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment involved in the targets were performed by the DAVID database and ClueGO plugin in Cytoscape. Finally, AutoDockTools software was used for molecular docking to verify the binding strength between main active ingredients and key target proteins. Results: A total of 22 main active ingredients such as quercetin, kaempferol, luteolin, and naringenin were obtained, which could act on 105 targets related to NS. Through PPI network, 53 core targets such as AKT1, TNF, IL6, VEGFA, and IL1B were found, which might play a crucial role in the treatment of NS. Meanwhile, these targets were significantly involved in PI3K-Akt signaling pathway, TNF signaling pathway, AGE-RAGE signaling pathway, hepatitis B, and pathways in cancer through GO and KEGG enrichment analysis. The docking results indicated that active ingredients such as kaempferol, luteolin, quercetin, and naringenin all had good binding to the target protein AKT1 or TNF. Among them, luteolin and naringenin binding with AKT1 showed the best binding energy (-6.2 kcal/mol). Conclusion: This study indicated that the potential mechanism of EH in treating NS may be related to PI3K-Akt signaling pathway, TNF signaling pathway, and AGE-RAGE signaling pathway, which provided better approaches for exploring the mechanism in treating NS and new ideas for further in vivo and in vitro experimental verifications.

Antioxidant and Antihyperglycemic Effects of Ephedra foeminea Aqueous Extract in Streptozotocin-Induced Diabetic Rats.

BACKGROUND: Ephedra foeminea is known in Jordan as Alanda and traditionally. It is used to treat respiratory symptoms such as asthma and skin rashes as an infusion in boiling water. The purpose of this study was to determine the antidiabetic property of Ephedra foeminea aqueous extract in streptozotocin-induced diabetic rats. METHODS: The aqueous extract of Ephedra foeminea plant was used to determine the potential of its efficacy in the treatment of diabetes, and this extract was tested on diabetic rats as a model. The chemical composition of Ephedra foeminea aqueous extract was determined using liquid chromatography-mass spectrometry (LC-MS). Antioxidant activity was assessed using two classical assays (ABTS and DPPH). RESULTS: The most abundant compounds in the Ephedra foeminea extract were limonene (6.3%), kaempferol (6.2%), stearic acid (5.9%), ß-sitosterol (5.5%), thiamine (4.1%), riboflavin (3.1%), naringenin (2.8%), kaempferol-3-rhamnoside (2.3%), quercetin (2.2%), and ferulic acid (2.0%). The antioxidant activity of Ephedra foeminea aqueous extract was remarkable, as evidenced by radical scavenging capacities of 12.28 mg Trolox/g in ABTS and 72.8 mg GAE/g in DPPH. In comparison to control, induced diabetic rats treated with Ephedra foeminea extract showed significant improvement in blood glucose levels, lipid profile, liver, and kidney functions. Interleukin 1 and glutathione peroxidase levels in the spleen, pancreas, kidney, and liver of induced diabetic rats treated with Ephedra foeminea extract were significantly lower than in untreated diabetic rats. CONCLUSIONS: Ephedra foeminea aqueous extract appears to protect diabetic rats against oxidative stress and improve blood parameters. In addition, it has antioxidant properties that might be very beneficial medicinally.

A Novel Anticancer Effect of Ephedra alata Decne in Breast Cancer Cells.

Cancer is a class of diseases characterized by uncontrolled cell growth. One of the main aims of developing new therapies is to use natural resources to induce apoptosis. LC-ms/ms analysis of a methanolic extract of Ephedra alata (E.A.) allowed the identification of 20 secondary metabolites, including flavonoids, phenolic acids, and proanthocyanidins. Antiproliferative effect was assessed by crystal violet assay. Antimigration effect was tested by wound healing assay and apoptosis induction was determined by annexin binding assays, Hoechst staining, ROS production, and activation of apoptotic proteins. The results indicated that exposure of breast cancer cells to E.A. extract significantly reduced cell viability in a dose and time-dependent manner and inhibited the migration of 4T1 cells at a low dose. Moreover, treatment of cells with E.A. extract induced apoptosis, as it was detected by Annexin V/7 AAD, Hoechst staining, ROS production, and the activation of caspases.Abbreviation:BSAbovine serum albuminDMSOdimethyl sulfoxideEDTAethylenediaminetetraacetic acidLC-ms/msliquid chromatography-mass spectrometryNACN-acetyl-l-cysteinePARPpoly(ADP-ribose) polymerasePMSFphenylmethylsulfonyl fluorideRIPAradioimmunoprecipitation assay bufferROSreactive oxygen speciesRPMIRoswell park memorial instituteSDS-PAGEsodium dodecyl sulfate-polyacrylamide gel electrophoresis.