Strobilanthes cusia (Nees) Kuntze, a multifunctional traditional Chinese medicinal plant, and its herbal medicines: A comprehensive review

In recent years, oxidative stress (OS) and the generation of ROS have been recognized as a fundamental pathology contributing, at least partially, to a number of important diseases. However, the therapeutic application has been simplistically limited to using antioxidants with little correction of diseases, and many biomarkers of OS, although confirming and quantifying the magnitude of this pathology, are not suggestive of the underlying causes behind generation of a large amount of free radicals.

Unfortunately, research has not noted the multi-implication parallel phenomenon of Ihtiraq (Combustion) in Unani Medicine, which possesses much richer etiopathological sub-typing and much more variegated selective and specific treatments (and prophylactics) corresponding to each sub-type of Ihtiraq; the identification of each sub-type's molecular counterparts can be used to develop not only sub-types of OS pathologies and corresponding selective treatments/prophylactics but also non-biomolecular factors.

Eminent Unani physicians described a deteriorative phenomenon, which they termed as ʻIhtiraqʼ which stands for extreme metabolism or ‘combustion’ and is recognized as a fundamental pathology, contributing as a major factor to the development of chronic diseases.

Further, Unani Medicine also possesses a pathophysiological phenomenon called ‘Hararat Ghariba’ (Unnatural Heat) whose diverse associations with Ihtiraq may be correlatable as upstream, parallel, or downstream associations of OS and consequent pathologies.

The aim of the study is to:

1. Explore the correlation of the phenomenon and etiopathology of Ihtiraq and OS and the treatment and prevention of the pathologies arising from them.

2. Extrapolate Ihtiraq, its types, causes, prevention, and treatment to OS, hitherto existing as a fundamental and monolithic pathology of increased ROS, to hypothesize its molecular-level sub-typing, as well as to propose selective interventions in these molecular sub-types of OS in place of the existing use of only basic antioxidants such as Vitamin C.

This review is presented with a noteworthy insight into Unani concepts and a thorough study of classical Unani literature by Ibn Sina (10th century), Zakaria Razi (9th century), Ibn Rushd (12th century), Ibn al-Nafees (13th century), Majusi (10th century), and Jurjani (11th century), and comparative detailed study of modern concepts of OS from literature databases, as well as Google, recent researches, and review articles.

The study showed very close correspondences between the phenomenon, etiopathology, and treatment and prevention of Ihtiraq in Unani Medicine and OS in contemporary biomolecular medicine. It also revealed sub-types of Ihtiraq and corresponding selective Unani treatments and prophylactics including drugs and non-drug factors.

After a comprehensive study and analysis of the most recent researches and classical theories, it can be stated that OS can be seen as a molecular level expression of Ihtiraq. Further, various components of Ihtiraq may be used to hypothesize molecular sub-types of OS and propose corresponding specific interventions.

Strobilanthes glutinosus (family: Acanthaceae) is one of the important medicinal plants and the current research work was carried out to assess the phytochemical, biological, and in-silico evaluations of different solvent extracts of S. glutinosus. The phytochemical composition was assessed by determining qualitative phytochemical testing, total bioactive contents, and GC-MS analysis. For biological evaluation, antioxidant (DPPH and FRAP), antibacterial, and enzyme inhibition (urease) potential were determined. The methanol extract was found to contain the highest total phenolic (247.85 mg GAE/g extract), and flavonoid content (71.91 mg QAE/g extract), which can be correlated to the observed higher antioxidant potential of this extract. On the contrary, the n-hexane extract presented maximum anti-urease activity with IC₅₀ value of 0.244 mg/ml, whereas, in the case of antibacterial assays, a dose-dependent activity was observed. Similarly, the GC-MS investigation of methanol extract and n-hexane fraction revealed the tentative identification of several important classes of secondary metabolites. Furthermore, the main compounds as identified by GC-MS were further studied for in-silico molecular docking studies in order to highlight any interactions between the compounds identified and the urease enzyme. Overall, the present investigation highlighted the studied plant extracts to be considered further for the isolation of bioactive compounds for the pharmaceutical and food industry.

Locally known as ‘pecah batu’, ‘bayam karang’, ‘keci beling’ or ‘batu jin’, the Malaysian medicinal herb, Strobilanthes crispus (S. crispus), is traditionally used by the local communities as alternative or adjuvant remedy for cancer and other ailments and to boost the immune system.

S. crispus has demonstrated multiple anticancer therapeutic potential in vitro and in vivo. A pharmacologically active fraction of S. crispus has been identified and termed as F3. Major constituents profiled in F3 include lutein and β-sitosterol.

In this study, the effects of F3, lutein and β-sitosterol on tumor development and metastasis were investigated in 4T1-induced mouse mammary carcinoma model.

Tumor-bearing mice were fed with F3 (100 mg/kg/day), lutein (50 mg/kg/day) and β-sitosterol (50 mg/kg/day) for 30 days (n = 5 each group). Tumor physical growth parameters, animal body weight and development of secondary tumors were investigated. The safety profile of F3 was assessed using hematological and histomorphological changes on the major organs in normal control mice (NM).

Our findings revealed significant reduction of physical tumor growth parameters in all tumor-bearing mice treated with F3 (TM-F3), lutein (TM-L) or β-sitosterol (TM-β) as compared with the untreated group (TM). Statistically significant reduction in body weight was observed in TM compared to the NM or treated (TM-F3, TM-L and TM-β) groups. Histomorphological examination of tissue sections from the F3-treated group showed normal features of the vital organs (i.e., liver, kidneys, lungs and spleen) which were similar to those of NM. Administration of F3 to NM mice (NM-F3) did not cause significant changes in full blood count values.

F3 significantly reduced the total tumor burden and prevented secondary tumor development in metastatic breast cancer without significant toxicities in 4T1-induced mouse mammary carcinoma model. The current study provides further support for therapeutic development of F3 with further pharmacokinetics studies.

Anti-angiogenesis is an important strategy of psoriasis treatment, but the side effects of systemic agents remain difficult to overcome. Topical use of indigo naturalis ointment has been proved to improve the skin lesion of psoriasis effectively and safely and one of its major components, tryptanthrin, has been demonstrated to have anti-angiogenic effect. Apelin, which has been reported to act as an angiogenic factor that could stimulate the proliferation and migration of vascular endothelial cells and proved to be elevated in psoriasis patients, is a potential target of anti-angiogenic therapy.

We aim to find out if tryptanthrin works on the apelin pathway and study its anti-angiogenic mechanism.

Human umbilical vein endothelial cells (HUVECs) were used as the in vitro model.

The effect of tryptanthrin on the expression of apelin and its receptor, APJ, was examined. The mRNA stability, promoter activity, and bioactivity of apelin, were also investigated. Migration and tube formation assay were used to evaluate the relationship between tryptanthrin and apelin. PD98059 and wortmannin were used to study the role of ERK1/2 MAPK and PI3K in apelin signaling pathway.

We demonstrated that tryptanthrin could inhibit the expression of apelin, attenuated the stability of apelin mRNA, and significantly inhibited the apelin promoter activity. The addition of apelin-13 restored the suppression of tube formation and migration by tryptanthrin. Both PD98059 and wortmannin could down-regulate the apelin mRNA expression suggesting the important signaling role of ERK1/2 MAPK and PI3K in the gene expression of apelin.

The anti-angiogenic effect of tryptanthrin was mediated by down-regulating apelin gene expression through suppression of promoter activity and decrease of mRNA stability in human vascular endothelial cells.

Xuebijing (XBJ) injection is a Chinese medicine containing extracts from Carthamus tinctorius L. (Carthami Flos, hong hua, Asteraceae), Paeonia lactiflora Pall. (Paeoniae radix rubra, chi shao, Ranunculaceae), Ligusticum chuanxiong Hort. (Chuanxiong Rhizoma, chuan xiong, Umbelliferae), Salvia miltiorrhiza Bge. (Salviae miltiorrhizae Radix Et Rhizoma, dan shen, Labiatae) and Angelica sinensis (Oliv.) Diels (Angelicae sinensis Radix, dang gui, Umbelliferae). It has been approved for the treatment of sepsis in China since 2004 and has been widely used as an add-on treatment for sepsis or septic shock with few side effects.

The aim of the present review was to analyse up-to-date information related to the treatment of sepsis with XBJ, including the bioactive constituents, clinical studies and potential mechanisms, and to discuss possible scientific gaps, to provide a reliable reference for future studies.

Scientific resources concentrating on treating sepsis with XBJ were searched through PubMed, the Chinese National Knowledge Infrastructure (CNKI) and WanFang databases from inception to November 2018. Dissertations were also searched, and eligible dissertations were selected. Studies related to the identification of constituents, bioactive components and their targets of action or pathways, clinical trials, and animal or cellular experiments that explored pharmacological mechanisms were manually selected. The quality of reporting and methodology of the included pharmacological experiments were assessed using the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines and the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)'s risk of bias tool.

A total of 108 relative studies were eventually included, containing 12 bioactivity research studies, 10 systematic reviews on clinical trials and 86 animal or cellular experiments. We noted that as identification methods progressed, further constituents could be detected in XBJ. XBJ was also found to have “multi-ingredient, multi-target and multi-pathway” effects. The systematic review revealed that XBJ could improve the 28-day mortality and other indexes, such as the APACHE II score, body temperature, and white blood cell (WBC) count, to some extent. A major organ protection effect was demonstrated in septic rats. Pharmacological investigations suggested that XBJ acts in both the early and late stages of sepsis by anti-inflammatory, anti-coagulation, immune regulation, vascular endothelial protection, anti-oxidative stress and other mechanisms. However, most of the included studies were poorly reported, and the risk of bias was unclear.

With respect to the multiple therapeutic mechanisms contributing to both the early and late stages of sepsis, the multiple effective constituents detected and randomized controlled trials (RCTs) performed to prove its efficacy, XBJ is a promising therapy for the treatment of sepsis. However, although XBJ has shown some efficacy for the treatment of sepsis, there are currently some scientific gaps. More studies concerning the pharmacokinetics, interactions with antibiotics, real-world efficacy and safety, pharmacological mechanisms of the bioactive components and large-scale clinical trials should be conducted in the future.

Qingre Zaoshi Liangxue Fang (QRZSLXF) is a Chinese medicinal herb recipe that is commonly prescribed for the treatment of ulcerative colitis. It includes 5 quality assured herbs: Sophora flavescens Aiton., Baphicacanthus cusia (Nees) Bremek., Bletilla striata Rchb.f., Glycyrrhiza uralensis Fisch. and Coptis chinensis Franch. The main phytochemical ingredient of QRZSLXF includes ammothamnine, sophocarpidine, liquiritin, berberine and indirubin. QRZSLXF has been clinically proven for use in the treatment of ulcerative colitis for over twenty years. In the past ten years, research has confirmed the therapeutic effect of QRZSLXF in ulcerative colitis and partially revealed its mechanism of action. Here, we further reveal the therapeutic mechanism of QRZSLXF in ulcerative colitis. To investigate the role of the DOR-β-arrestin1-Bcl-2 signal transduction pathway in ulcerative colitis and to determine the effects of QRZSLXF on this signal transduction pathway.

Eighty-four Sprague-Dawley rats were randomly divided into six groups: normal control group, model group, mesalazine group, and QRZSLXF high-dose, medium-dose group and low-dose groups (n=14). Experimental colitis was induced by trinitrobenzenesulfonic acid (TNBS) in each group, except the normal control group. After modeling, bloody stool, mental state and diarrhea were observed and recorded. Two rats were randomly selected from the model groups adfnd sacrificed on day 3 to observe pathological changes in the colon tissue by microscopy. The rats in the QRZSLXF-treated groups received intramuscular injections of different concentrations of QRZSLXF for 15 days. The rats in the mesalazine group were treated with mesalazine solution (0.5 g/kg/day) by gastric lavage for 15 days. The rats in the normal control group and the model group were treated with 3 mL water by gastric lavage for 15 days. On the 16th day, after fasting for 24 h, the remaining rats were sacrificed and their colon tissues were used to detect the mRNA and protein expressions of DOR, β-arrestin1 and Bcl-2 by Real-time PCR and immunohistochemistry, respectively. Histological changes in the colon tissues were also examined.

The expressions of DOR, β-arrestin1 and Bcl-2 were significantly different among the four groups. The expressions of DOR, β-arrestin1 and Bcl-2 protein and mRNA were significantly increased in the model group compared with the other groups (P<0.05). In contrast to the model group, the expressions of DOR, β-arrestin1 and Bcl-2 were significantly decreased in the mesalazine group and the groups that received different doses of QRZSLXF (P<0.05), and there were no statistically significant differences among the mesalazine and QRZSLXF-treated groups (P>0.05). This study indicates that the DOR-beta-arrestin1-Bcl-2 signal transduction pathway may participate in the pathologic course of ulcerative colitis. Moreover, QRZSLXF could attenuate ulcerative colitis by regulating the DOR-β-arrestin1-Bcl-2 signal transduction pathway.