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Veratrazine A, a steroidal alkaloid with a unique 6/5/5 triheterocyclic scaffold as the side chain, was isolated from the roots of Veratrum stenophyllum and exhibited moderate and dose-depended anti-inflammatory activities in vitro and in vivo.

Alstolactines D (1) and E (2), two unprecedented indole alkaloids with an aziridine scaffold, exhibited significant anti-inflammatory bioactivity.

A new class of natural sesquiterpenes with a 2-(tetrahydro-2H-pyran-2-yl)propan-2-ol system from the fungus Bipolaris cynodontis DJWT-01. Bipodonines A and B featuring γ- and δ-lactone might be degradative derivatives of polyketide–terpenoid.

Tuberindines A and B (

Hyperectumine (1), the first C19 benzylisoquinoline alkaloid with a complicated ring system, was isolated from Hypecoum erectum and structurally characterized. Its biosynthetic origin should involve a hybrid pattern of C8 + C8 + C1 + C2, from which a C17 benzylisoquinoline alkaloid might be further attacked by a malonamic acid and undergo decarboxylation and cyclization to produce 1. Compound (-)-1 exhibited moderate anti-inflammatory activity via suppression of LPS-activated inflammatory mediators in RAW 264.7 macrophage cells.

Two rearranged triterpenoids, representing new subtypes of pentacyclic triterpenoids, with unique 6/6/6/7/5 and 6/6/5/6/6/6 ring systems were isolated from Alstonia scholaris. Their structures were established by spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Both compounds exhibited potent antihyperuricemic bioactivity in vitro and in vivo.

Chaenomeles speciosa (Sweet) Nakai is a dual-purpose Chinese herbal medicine and functional food favored by minorities in Southwest China, and its fruits are used for the treatment of dyspepsia, dysentery, enteritis, and rheumatism inflammation. Some diseases may be related to microbial infection; however, it is not known how the fruits possess antimicrobial activity. We evaluated the antimicrobial bioctivity of different evaluation extracts of C. speciosa fruits by in vitro and in vivo with colony-forming unit assays, and the strongest bioactive-guided fraction was selected for column chromatography (CC), UHPLC-QTOF-MS/MS, and NMR spectroscopy to confirm the chemical constituents. The most possible antimicrobial mechanism of C. speciosa fruits was explored by metabolomics approach, fluorescence microscopy imaging, and scanning electron microscopy (SEM). Thirty compounds, which were major characteristic ions of the bioactive fraction, were determined precisely. The bioactive fraction could inhibit 18 pathogenic microorganisms, significantly reduced, especially drug-resistant bacteria, compared to ampicillin sodium salt, fluconazole, and berberine chloride form; and the minimum inhibitory concentration (MIC) or minimum fungicidal concentration (MFC) values were in the range of 0.1-1 mg/mL. The compounds 2'-methoxyaucuparin (1) and oleanolic acid (20) not only have antibacterial activity but also may have synergistic effects. Further, the bioactive fraction might inhibit the biofilm formation, enhance immunity, and restore bacterial infection damage in vitro and in vivo to kill microorganisms. The data indicated that C. speciosa fruits' major bioactive fraction enriched with triterpenes, flavonoids, and phenolics could be developed as a functional supplement for individuals to prevent and treat microbial infection.

Context Capsule of alkaloids from the leaf of Alstonia scholaris (L.) R.Br. (Apocynaceae) (CALAS) is a new investigational botanical drug (No. 2011L01436) for bronchitis, post-infectious cough and asthma. Objective To observe the clinical safety and tolerability of CALAS. Materials and methods Subjects were assigned to eight cohorts, and each received randomly CALAS or placebo in one of single ascending dose (SAD) of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose (MAD) of 40 or 120 mg, three times daily for 7 days. Each cohort contained two placebo subjects. Results Sixty-two enrolled volunteers completed the study and no serious adverse events and clinically significant changes in vital signs, electrocardiography, and upper abdominal Doppler ultrasonography were observed. The ratios of treatment-emergent adverse events (TEAEs) were reported in 11/46 (23.91%) of CALAS groups and 3/16 (18.75%) of the placebo group (p > 0.05), respectively, based on the results of SAD and MAD. All TEAEs were mild, transient, and disappeared without any intervention. The TEAEs possibly related to CALAS treatment were as followings: hiccups (4/46: 8%), dry mouth and nausea (3/46: 6%), increased sleep (2/46: 4%), abdominal distension (1/46: 2%), bilirubin elevated (1/46: 2%). Discussion and conclusions CALAS is safe and well-tolerated with no unexpected or clinically relevant safety concerns up to a single dose of 360 mg and three times daily for 7 days up to 120 mg in healthy Chinese volunteers, supporting further Phase II studies.

Alstonia scholaris could be used as a traditional medicinal plant in China for the treatment of acute respiratory, which might be caused by respiratory tract infections. The investigation tested the anti-infective effects of total alkaloids extract (TA) from leaves of A. scholaris, and as a result, TA inhibited herpes simplex virus type 1 (HSV-1), respiratory syncytial virus (RSV) and influenza A virus (H1N1) in vitro respectively. In addition, the survival days of mice were prolonged, and the lung weights and mortality of mice were decreased significantly, after oral administrated TA in H1N1 and beta-hemolytic streptococcus infectious models in vivo respectively. The finding supported partly the traditional usage of A. scholaris in the treatment of respiratory infections. Graphic Abstract

Clerodendranthus spicatus, popularly known as "kidney tea" in China, is consumed traditionally as a functional food for treatment of renal inflammation, dysuria, and gout. We evaluated the effects of C. spicatus on gout by assessing activities of antihyperuricemia, anti-gouty arthritis, and analgesia in vivo, and the results indicated that the ethyl acetate fraction shows potential activities. Subsequent phytochemical investigation of this fraction led to the isolation of 32 compounds, consisting of 20 diterpenoids (including the new orthosiphonones E and F), 2 triterpenoids, 6 flavonoids, 2 lignanoids, and 2 phenolic acid derivatives. Pharmacological investigation of the pure compounds in the cellular model of hyperuricemia indicated that 12 compounds could promote the excretion of uric acid at 10 μg/mL, and compounds 3, 4, 5, and 21 had better effects than that of benzbromarone, a famous uricosuric drug. Furthermore, compounds 4, 6, 7, 9, 14, 15, 23, 26, and 31 showed significant anti-gouty arthritis activity in monosodium urate (MSU)-induced joint swelling at the dose of 50 mg/kg, while compounds 4, 5, 7, 9, and 26 exhibited significant inhibition of pain induced by acetic acid. Our findings provided scientific justification to support the traditional application of "kidney tea" for treating gout and suggested its good application prospects in the future.

Alstonia scholaris (L.) R. Br., an evergreen tropical plant rich in indole alkaloids with significant physiological activity, is traditionally used to treat respiratory diseases in China. This study was conducted to establish the toxicity profile of the alkaloid extract (TA) of A. scholaris leaves in non-rodents. After oral administration of a single dose (4 g/kg.bw), a number of transient symptoms, such as unsteady gait, drooling, emesis, and reddening of peri-oral mucosa, were observed, but no treatment-related mortality. A sub-chronic toxicity study with a range of doses of TA (20, 60 and 120 mg/kg.bw) was conducted for a 13-week treatment period, followed by 4-week recovery observation. Except for emesis and drooling in majority of animals in 120 mg/kg.bw treatment group, no clinical changes were observed in TA-treated animals. Data from electrocardiography, bone marrow, urine, fecal, hematology and clinical chemistry analyses were comparable between TA-treated and control animals. No significant differences in the relative organ weights and histopathological characteristics were evident between the TA-treated and control groups. Accordingly, the non-observed-adverse-effect-level (NOAEL) of TA was established as 120 mg/kg.bw. Our results add further knowledge to the safety database for indole alkaloid extracts from A. scholaris with potential utility as novel drug candidates. Graphic Abstract

Abstract Indole alkaloids extract (IAAS) was prepared from leaves of Alstonia scholaris (L.) R. Br., an evergreen tropical plant widely distributed throughout the world. This plant has been used historically by the Dai ethnic people of China to treat respiratory diseases. This study evaluated the genotoxicity and safety pharmacology of IAAS to support clinical use. The bacterial reverse mutation (Ames) test, in vitro mammalian chromosomal aberration test, and in vivo mammalian erythrocyte micronucleus (MN) test were performed to evaluate genotoxicity. Mice were administered IAAS (240, 480, or 960 mg/kg bw) once orally to observe adverse central nervous system effects. Furthermore, beagle dogs were administered IAAS (10, 30, 60 mg/kg bw) once via the duodenum to evaluate its effects on the cardiovascular and respiratory systems. IAAS with or without S9-induced metabolic activation showed no genotoxicity in the Ames test up to 500 μg/plate, in the mammalian chromosomal aberration test up to 710 μg/mL, or in the MN test up to 800 mg/kg bw. No abnormal neurobehavioral effects were observed in mice following treatment with up to 960 mg/kg bw of IAAS. Moreover, blood pressure, heart rate, electrocardiogram parameters, and depth and rate of breathing in anesthetized beagle dogs did not differ among the IAAS doses or from the vehicle group. These data indicated that IAAS did not induce mutagenicity, clastogenicity, or genotoxicity, and no pharmaco-toxicological effects were observed in the respiratory, cardiovascular, or central nervous systems. Our results increased understanding of safety considerations associated with IAAS, and may indicate that IAAS is a possible drug candidate. Graphic Abstract

The fruits of Lycium barbarum have a long history as an edible and medicinal food in Asian regions and have multiple consumption methods; the polysaccharides (LBPs) are commonly considered as their major immunological constituents. The current study revealed that the total phenolic amide moieties from L. barbarum fruits showed greater potential immunomodulatory activity in vivo than did LBPs. Through subsequent investigation on the immunological bioactive phenolic amides, three new phenolic amides, lyciumamides L-N (1-3), as well as 12 analogues, were obtained from the total phenolic amide fraction. Extensive spectroscopic methods were used to elucidate the new structures. Compounds 4-6 and 15 significantly promoted LPS-stimulated B splenocyte, while compounds 4-6 displayed accelerative effects on the proliferation of Con A-stimulated T lymphocytes at a concentration of 20.0 μg/mL. These data indicated that extracts from L. barbarum fruits enriched with phenolic amides could be developed as a nutritional dietary supplement for immunocompromised individuals.

Hyperectumine (

Hyperuricemia is a metabolic disease caused by impaired uric acid (UA) metabolism. Ellagic acid (EA) is a natural small-molecule polyphenolic compound with known antioxidative and anti-inflammatory properties. Here, we evaluated the regulatory effects of EA on hyperuricemia and explored the underlying mechanisms. We found that EA is an effective xanthine oxidase (XOD) inhibitor (IC50 = 165.6 μmol/L) and superoxide anion scavenger (IC50 = 27.66 μmol/L). EA (5 and 10 μmol/L) treatment significantly and dose-dependently reduced UA levels in L-O2 cells; meanwhile, intraperitoneal EA administration (50 and 100 mg/kg) also significantly reduced serum XOD activity and UA levels in hyperuricemic mice and markedly improved their liver and kidney histopathology. EA treatment significantly reduced the degree of foot edema and inhibited the expression of NLPR3 pathway-related proteins in foot tissue of monosodium urate (MSU)-treated mice. The anti-inflammatory effect was also observed in lipopolysaccharide-stimulated RAW-264.7 cells. Furthermore, EA significantly inhibited the expressions of XOD and NLRP3 pathway-related proteins (TLR4, p-p65, caspase-1, TNF-α, and IL-18) in vitro and in vivo. Our results indicated that EA exerts ameliorative effects in experimental hyperuricemia and foot edema via regulating the NLRP3 signaling pathway and represents a promising therapeutic option for the management of hyperuricemia.

Acute lung injury (ALI), a severe respiratory disorder, frequently develops into acute respiratory distress syndrome (ARDS) without timely treatment and scores highly in terms of morbidity and mortality rates. Fritillaria hupehensis is a famous traditional Chinese medicine with antitussive, expectorant and anti-asthmatic effect. Here, the effects of F. hupehensis extracts on lipopolysaccharide (LPS)-induced ALI mice were evaluated for the first time. We showed ethyl acetate fraction (EAF) significantly reduced the leukocytes and neutrophils of bronchoalveolar lavage fluid (BALF) and the lung index as well as pro-inflammatory cytokines (TNF-α and IL-6) of lung homogenates but increasing the anti-inflammatory cytokines (IL-4 and IL-10). Additionally, the alleviation of EAF treatment on lung injury was verified through histopathological observations. Subsequent phytochemical investigation on bioactive fraction led to isolation of 17 compounds including two new, in which compounds 2, 5 and 6 exhibited better anti-inflammatory effect on LPS-induced 16 human airway epithelial (16HBE) cells model by inhibiting the production of CRP and PCT. Furthermore, compound 2 suppressed the LPS-induced upregulation of proteins containing p-p65, COX-2, Caspase-1 and IL-18. In summary, F. hupehensis alleviating LPS-induced ALI in mice may be associated with the anti-inflammatory activity of steroidal alkaloids by suppressing the NF-κB-regulated pro-inflammatory proteins.

Two distinctive alkaloids with 6/6/6/5/6/6 fused rings, in which a previously unidentified linkage of C-12/23 generates a rigid skeleton, resulting in a new subtype of steroidal alkaloid, were isolated from Veratrum grandiflorum. Compounds 1 and 2 showed potent analgesic effects in vivo, superior to the well-known analgesic, pethidine (Dolantin), likely by inhibiting CaV2.2 voltage-gated calcium channels.

Ethnopharmacological relevance “Ya gai”, an important part of Dai medical theory, is traditionally recognized as an antidote. Kopsia officinalis Tsiang et P. T. Li is a “Ya gai” related medicine and has been widely used by Dai people for the treatment of pain and inflammation. Previous literature on title species suggested that monoterpenoid indole alkaloids (MIAs) could be its main bioactive components. However, the specific bioactive ingredients for inflammation-related treatment are still unrevealed, which inspired us to conduct a phytochemical and pharmacological investigation related to its traditional use. Aim of the study To support the traditional use of K. officinalis by assessing the anti-inflammatory and analgesic effects of its purified MIAs. Material and methods Compounds were isolated and purified from the barks and leaves of K. officinalis using diverse chromatographic methods. The structures were established by means of extensive spectroscopic analyses and quantum computational technique. The anti-inflammatory activities of the purified MIAs were evaluated in vitro based on the suppression of lipopolysaccharide-activated inflammatory mediators (COX-2, IL-1β, and TNF-α) in RAW 264.7 macrophage cells. Anti-inflammatory and analgesic activities in vivo were assessed with carrageenan-induced paw edema and acetic acid-stimulated writhing in mice models. Results 23 MIAs including four new compounds were obtained and structurally established. Most of isolates showed significant anti-inflammatory effects in vitro by inhibiting inflammatory mediators (COX-2, IL-1β, and TNF-α). Further pharmacological evaluation in vivo revealed that 12-hydroxy-19(R)-hydroxy-ibophyllidine (1) and 11,12-methylenedioxykopsinaline N4-oxide (5) remarkably decreased the number of writhing, while kopsinic acid (8), (−)-kopsinilam (12), and normavacurine-21-one (20) significantly relieved paw edema, respectively, even better than the positive control aspirin. Conclusions The in vitro and in vivo findings supported the traditional use of K. officinalis with respect to its anti-inflammatory and analgesic effect, as well as provided potent bioactive MIAs for further chemical modification and pharmacological investigation.

Capsule of alkaloids from leaf of Alstonia scholaris (CALAS) is a new investigational botanical drug (No. 2011L01436) for respiratory disease. Clinical population pharmacokinetics (PK), metabolomics and therapeutic data are essential to guide dosing in patients. Previous research has demonstrated the potential therapeutic effect of CALAS on acute bronchitis. Further clinical trial data are needed to verify its clinical efficacy, pharmacokinetics behavior, and influence of dosage and other factors.To verify the clinical efficacy and explore the potential biomarkers related to CALAS treatment for acute bronchitis.Oral CALAS was assessed in a randomized, double-blind, placebo-controlled trial. Fifty-five eligible patients were randomly assigned to four cohorts to receive 20, 40 or 80 mg, of CALAS three times daily for seven days, or placebo. Each CALAS cohort included 15 subjects, and the placebo group included 10 subjects. A population PK model of CALAS was developed using plasma with four major alkaloid components. Metabolomics analysis was performed to identify biomarkers correlated with the therapeutic effect of CALAS, and efficacy and safety were assessed based on clinical symptoms and adverse events.The symptoms of acute bronchitis were alleviated by CALAS treatment without serious adverse events or clinically significant changes in vital signs, electrocardiography or upper abdominal Doppler ultrasonography. Moreover, one compartment model with first-order absorption showed that an increase in aspartate transaminase will reduce the clearance (CL) of scholaricine, and picrinine CL was inversely proportional to body mass index, while 19-epischolaricine and vallesamine CL increased with aging. The serum samples from acute bronchitis patients at different time points were analyzed using UPLC-QTOF in combination with the orthogonal projection to latent structures-discriminant analysis, which indicated higher levels of lysophosphatidylcholines, lysophosphatidylethanolamines and amino acids with CALAS treatment than with placebo.This is the first study to evaluate the clinical efficacy and explored the potential biomarkers related to CALAS therapeutic mechanism of acute bronchitis by means of clinical trial combined the metabolomics study. This exploratory study provides a basis for further research on clinical efficacy and optimal dosing regimens based on pharmacokinetics behavior. Additional acute bronchitis patients and CALAS PK samples collected in future studies may be used to improve model performance and maximize its clinical value.

Dactylicapnosines A (1) and B (2), two reconstructed aporphines with unprecedent five-membered carbon ring D, were isolated from Dactylicapnos scandens, in which dactylicapnosine A showed potent anti-inflammatory bioactivity in vitro. Inspired by its biosynthetic pathway, the total synthesis of dactylicapnosine A via 10 steps has been achieved and afforded enough material to prove its significant anti-inflammatory effect in vivo.

Two new Tricholoma terpenoids, tricholopardins A and B, were isolated from the fruiting bodies of the basidiomycetes Tricholoma pardinum. Their structures were elucidated by spectroscopic methods, as well as electronic circular dichroism and optical rotatory dispersion calculations. Tricholopardin A potently inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophages with an IC50 of 0.08 μM. Its anti-inflammatory effects on three inflammatory mediators were also evaluated. A plausible biosynthetic pathway for these products is discussed.

In recent years, the T-cell therapy and immune checkpoint inhibitors toward CTLA-4 and PD-1/PD-L1 axis antibody therapy have acquired encouraging success. However, most of patients were still not benefited with lots of troubles, such as low penetration of tissues/cells, strong immunogenicity and cytokine release syndrome, and long manufacturing process and expensive costs. By contrast, the immune-modulating small molecules possessed natural advantages to overcome these obstacles and might achieve greater success.Exploring the potent immune-modulating natural small molecules and revealing what kinds of molecules or structures with the immunomodulatory activity against cancers.A novel non-cytotoxic T-cell immunomodulating screening model was used to identify the cytotoxic/selective/immunomodulatory bioactivity for 148 natural steroidal saponins. The structure-activity relationships (SARs) research was used to reveal the key groups for immunomodulation/cytotoxicity/selectivity. The negative selection was used to isolate and purify the T-cell. The cell viability assay was used to measure the anti-cancer effect in vitro. The ELISA assay was used to detect the cytokines for IL-1β, IL-6, TNF-α, IFN-γ, IL-12, perforin and granzyme B (GZMB). The western blotting assay was used to research the immunomodulatory mechanism. The siRNA knockdown was used to generate the IFN-γ resistant melanoma cells. The NOG immune-deficient mice were used to evaluate the anti-tumor efficacy in vivo. The peripheral blood samples from 10 cancer patients were used to detect the broad population anti-tumor efficacy.It was reported that the correlation among structures and immunomodulation/ cytotoxicity/selectivity, in which opening ring-F with 26-O-glucopyranosyl, disaccharide and trisaccharide chains at C-3, steric hindrance and polarity of C-22 were key immunomodulatory groups. Moreover, taccaoside A was identified as the most potent candidate against cancer cells, including non-small cell lung cancer, triple negative breast cancer, and the IFN-γ resistant melanoma, partly through enhancing T lymphocyte mTORC1-Blimp-1 signal to secrete GZMB. Besides, 10 patients derived T-cell also would be modulated against cancer cells in vitro. Moreover, the overall survival was great extended (140 days vs 93 days) with nearly 100% tumor burden disappearance (0 mmThis work demonstrated one possibility for this concerned purpose, and identified a potent immune-modulating natural molecule taccaoside A, which might contribute to cancer immunotherapy in future.

"Li-Lu", the roots and rhizomes of Veratrum grandiflorum (Melianthiaceae), has been historically used as a traditional folk medicine for the treatment of wrist pain, fractures, sores, and inflammation in Yunnan Province, China. However, the anti-inflammatory and analgesic studies of this plant have seldom reported.To evaluate the anti-inflammatory and analgesic properties related to the traditional usage of V. grandiflorum both in vitro and in vivo, and further explore the accurate bioactive compounds from the medicinal plant.Phytochemical investigation was carried out by chromatographic methods and their structures were established based on extensive spectra and comparison with corresponding data in the reported literatures. Anti-inflammatory activities were assessed by the suppression of lipopolysaccharide-activated inflammatory mediators in RAW 264.7 macrophage cells in vitro. Furthermore, anti-inflammatory and analgesic effects were evaluated based on carrageenan-induced paw edema and acetic acid-stimulated writhing in mice.The methanol extract (ME) of V. grandiflorum significantly alleviated the paw edema caused by carrageenan and the writhing numbers induced by acetic acid. Subsequent phytochemical investigation led to isolated of 21 steroidal alkaloids, including seven new compounds, veragranines C-I (1-7). Anti-inflammatory test indicated that steroidal alkaloids could decrease the expression of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells at a concentration of 5.0 μg/ml in vitro, comparable to DXM. Moreover, five new steroidal alkaloids (2, 4, 5, 6, and 7) and two major steroidal alkaloids (9 and 13) significantly decreased the numbers of writhing in mice at the doses of 0.5 and/or 1.0 mg/kg (p 0.01/0.05), roughly comparable to Dolantin™ at 10.0 mg/kg.The investigation supported the traditional use of V. grandiflorum and provided new steroidal alkaloids as potent analgesic agents.

Sweet potato (Ipomoea batatas L.) is one of the leading crops worldwide, containing high nutritional components such as fiber and polyphenols. Root tuber of Simon 1 (SIMON), a cultivar of sweet potato, is a folk food in China with a hemostasis function but lacking experimental data support.Now the protective effect of SIMON on chemotherapy-induced thrombocytopenia (CIT), a serious complication of cancer treatment, is investigated for the first time by a CIT mouse model induced by intraperitoneal injection of carboplatin. As a result, SIMON raises the number of peripheral platelets, white blood cells, and bone marrow nucleated cells in CIT mice significantly. Besides, carboplatin-induced atrophy of the thymus, spleen, and disordered metabolism of the inflammatory immune system and glycerophospholipids are also reversed by SIMON. Phytochemical analysis of SIMON indicates 16 compounds including eight phenolic derivatives, which might be associated with its anti-CIT bioactivity.Sweet potato (SIMON) may be an efficient function food in the prevention of bleeding disorders.