Mechanisms for the biological activity of Gastrodia elata Blume and its constituents: A comprehensive review on sedative-hypnotic, and antidepressant properties.

BACKGROUND: Insomnia and depressive disorder are two common symptoms with a reciprocal causal relationship in clinical practice, which are usually manifested in comorbid form. Several medications have been widely used in the treatment of insomnia and depression, but most of these drugs show non-negligible side effects. Currently, many treatments are indicated for insomnia and depressive symptom, including Chinese herbal medicine such as Gastrodia elata Blume (G. elata), which has excellent sedative-hypnotic and antidepressant effects in clinical and animal studies. PURPOSE: To summarize the mechanisms of insomnia and depression and the structure-activity mechanism for G. elata to alleviate these symptoms, particularly by hypothalamic-pituitary-adrenal (HPA) axis and intestinal flora, aiming to discover new approaches for the treatment of insomnia and depression. METHODS: The following electronic databases were searched from the beginning to November 2023: PubMed, Web of Science, Google Scholar, Wanfang Database, and CNKI. The following keywords of G. elata were used truncated with other relevant topic terms, such as depression, insomnia, antidepressant, sedative-hypnotic, neuroprotection, application, safety, and toxicity. RESULTS: Natural compounds derived from G. elata could alleviate insomnia and depressive disorder, which is involved in monoamine neurotransmitters, inflammatory response, oxidative stress, and gut microbes, etc. Several clinical trials showed that G. elata-derived natural compounds that treat depression and insomnia have significant and safe therapeutic effects, but further well-designed clinical and toxicological studies are needed. CONCLUSION: G. elata exerts a critical role in treating depression and insomnia due to its multi-targeting properties and fewer side effects. However, more clinical and toxicological studies should be performed to further explore the sedative-hypnotic and antidepressant mechanisms of G. elata and provide more evidence and recommendations for its clinical application. Our review provides an overview of G. elata treating insomnia with depression for future research direction.

Borneol exerts its antipruritic effects by inhibiting TRPA1 and activating TRPM8.

ETHNOPHARMACOLOGICAL RELEVANCE: Borneol is a long-established traditional Chinese medicine that has been found to be effective in treating pain and itchy skin. However, whether borneol has a therapeutic effect on chronic itch and its related mechanisms remain unclear. AIM OF THE STUDY: To investigate the antipruritic effect of borneol and its molecular mechanism. MATERIALS AND METHODS: DrugBAN framework and molecular docking were applied to predict the targets of borneol, and the calcium imaging or patch-clamp recording analysis were used to detect the effects of borneol on TRPA1, TRPM8 or TRPV3 channels in HEK293T cells. In addition, various mouse models of acute itch and chronic itch were established to evaluate the antipruritic effects of borneol on C57BL/6J mice. Then, the borneol-induced pruritic relief was further investigated in Trpa1-/-, Trpm8-/-, or Trpa1-/-/Trpm8-/- mice. The effects of borneol on the activation of TRPM8 and the inhibition of TRPA1 were also measured in dorsal root ganglia neurons of wild-type (WT), Trpm8-/- and Trpv1-/- mice. Lastly, a randomized, double-blind study of adult patients was conducted to evaluate the clinical antipruritic effect of borneol. RESULTS: TRPA1, TRPV3 and TRPM8 are the potential targets of borneol according to the results of DrugBAN algorithm and molecular docking. Calcium imaging and patch-clamp recording analysis demonstrated that borneol activates TRPM8 channel-induced cell excitability and inhibits TRPA1 channel-mediated cell excitability in transfected HEK293T cells. Animal behavior analysis showed that borneol can significantly reduce acute and chronic itch behavior in C57BL/6J mice, but this effect was eliminated in Trpa1-/-, Trpm8-/- mice, or at least in Trpa1-/-/Trpm8-/- mice. Borneol elicits TRPM8 channel induced [Ca2+]i responses but inhibits AITC or SADBE-induced activation of TRPA1 channels in dorsal root ganglia neurons of WT and Trpv1-/- mice, respectively. Furthermore, the clinical results indicated that borneol could reduce itching symptoms in patients and its efficacy is similar to that of menthol. CONCLUSION: Borneol has therapeutic effects on multiple pruritus models in mice and patients with chronic itch, and the mechanism may be through inhibiting TRPA1 and activating TRPM8.

A telomere-to-telomere reference genome provides genetic insight into the pentacyclic triterpenoid biosynthesis in Chaenomeles speciosa.

Chaenomeles speciosa (2n = 34), a medicinal and edible plant in the Rosaceae, is commonly used in traditional Chinese medicine. To date, the lack of genomic sequence and genetic studies has impeded efforts to improve its medicinal value. Herein, we report the use of an integrative approach involving PacBio HiFi (third-generation) sequencing and Hi-C scaffolding to assemble a high-quality telomere-to-telomere genome of C. speciosa. The genome comprised 650.4 Mb with a contig N50 of 35.5 Mb. Of these, 632.3 Mb were anchored to 17 pseudo-chromosomes, in which 12, 4, and 1 pseudo-chromosomes were represented by a single contig, two contigs, and four contigs, respectively. Eleven pseudo-chromosomes had telomere repeats at both ends, and four had telomere repeats at a single end. Repetitive sequences accounted for 49.5% of the genome, while a total of 45 515 protein-coding genes have been annotated. The genome size of C. speciosa was relatively similar to that of Malus domestica. Expanded or contracted gene families were identified and investigated for their association with different plant metabolisms or biological processes. In particular, functional annotation characterized gene families that were associated with the biosynthetic pathway of oleanolic and ursolic acids, two abundant pentacyclic triterpenoids in the fruits of C. speciosa. Taken together, this telomere-to-telomere and chromosome-level genome of C. speciosa not only provides a valuable resource to enhance understanding of the biosynthesis of medicinal compounds in tissues, but also promotes understanding of the evolution of the Rosaceae.

TRPA1 is involved in the inhibitory effect of Ke-teng-zi on allergic contact dermatitis via MAPK and JAK/STAT3 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Entada phaseoloides (Linn.) Merr. commonly named "Ke-teng-zi" is a traditional Chinese folk medicine and reported to treat dermatitis, spasm, and headache. However, the exact effect and the mechanism of Ke-teng-zi on the treatment of dermatitis is unclear. AIM OF THE STUDY: To elucidate the antipruritic effect and molecular mechanisms of Ke-teng-zi on the treatment of allergic contact dermatitis (ACD). MATERIALS AND METHODS: The main components of the n-butanol fraction of 70% ethanol extract from Ke-teng-zi (abbreviated as KB) were analyzed by HPLC. The chloroquine (CQ)-induced acute itch and squaraine dibutyl ester (SADBE)-induced ACD chronic itch in mice was established, and the TNF-α/IFN-γ stimulated Human keratinocytes (HaCaT) were used to evaluate the antipruritic and anti-inflammatory effects of KB. Behavioral tests, lesion scoring, and histology were also examined. The expression levels of molecules in MAPK and JAK/STAT3 pathways, the mRNA levels of chemokines and cytokines in both the skin of ACD mice and the HaCaT cells were detected by western blot and qPCR. Furthermore, whole-cell patch-clamp recordings in TRPA1-tranfected HEK293T cells were used to elucidate the effect of KB on TRPA1 channels. TRPA1 siRNA was used to evaluate the role of TRPA1 in the anti-inflammatory effect of KB in keratinocytes. RESULTS: The main compounds in KB could bind to the active sites of TRPA1 mainly through hydrogen bond and hydrophobic bond interactions. KB could inhibit the scratching behavior in CQ-induced acute itch, and the inhibitory effect of KB was blocked by TRPA1 inhibitor HC-030031. In addition, KB significantly decreased the scratching bouts of ACD mice, reduced the skin lesion scores, mast cells degranulation, and epidermal thickening, inhibited the production of inflammatory chemokines/cytokines and CGRP, and down-regulated the levels of p-ERK1/2, p-p38, and p-STAT3, compared to the ACD mice. Moreover, continuous application of KB induced the desensitization of TRPA1 channels. Also, KB inhibited the expression of p-ERK1/2, p-p38, and p-STAT3, and down-regulated the expression of inflammatory chemokines and cytokines in vitro, which were reversed by the TRPA1 siRNA. CONCLUSIONS: KB alleviated the pruritus and skin inflammation in ACD mice through TRPA1 channels desensitization and down-regulation of intracellular MAPK and JAK/STAT3 signaling pathways. Our results suggested that Ke-teng-zi is a potential drug for the treatment of inflammatory skin diseases such as ACD.

Tibetan medicine Si-Wei-Qiang-Wei Powder ameliorates cholecystitis via inhibiting the production of pro-inflammatory cytokines and regulating the MAPK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Wei-Qiang-Wei Powder (SWQ) is a formulated traditional Tibetan medicine preparation that has been used clinically to treat liver and gallbladder diseases for centuries. Previous work has confirmed its clinical effectiveness, however, the specific mechanism of SWQ is still unknown. AIM OF THE STUDY: This study aims to explore the anti-inflammatory effect of SWQ on cholecystitis and its possible mechanism. MATERIALS AND METHODS: The main chemical components of SWQ were analyzed by HPLC. The network pharmacology database was used to screen and construct the network of the main components and molecular targets of SWQ, and to predict the molecular pathways of its core targets. Cholecystitis guinea pig model and LPS stimulated cultured human gallbladder epithelial cells (HGBEC) were used, as in vivo and in vitro methods respectively, to study the anti-cholecystitis activity of SWQ. Specifically, gallbladder wall thickness, hematoxylin-eosin (H&E) staining, and liver function indexes were used to evaluate the anti-inflammatory activities of SWQ in cholecystitis; qRT-PCR and ELISA were used to detect the changes of the production of inflammatory cytokines; Western blot analysis was used to analyze the effects of SWQ on phosphorylation of P38, ERK1/2, JNK and AKT. RESULTS: SWQ decreased the indexes of ALT, AST, TBA, CHOL, DBIL in serum and TBIL, TC and Ca2+ in bile, and alleviated the wall thickness of gallbladder and hepatobiliary fibrosis in LCA-induced guinea pigs. In addition, SWQ attenuated the expression and production of TNF-α, IL-6, IL-1ß, COX-2 both in liver and gallbladder. Moreover, SWQ reversed the up-regulation of p-P38, p-ERK1/2, and p-JNK in animals with cholecystitis and LPS-induced HGBEC. Furthermore, mechanistic studies indicated that SWQ inhibited the activation of ERK1/2, thereby decreasing the expression of TNF-α, IL-6, IL-1ß and phosphorylation P38 and JNK. CONCLUSION: In summary, our research showed that SWQ relieves gallbladder inflammation by inhibiting the MAPK pathway.

Anti-inflammatory and osteoprotective effects of Shi-Wei-Ru-Xiang pills on collagen-induced arthritis in rats via inhibiting MAPK and STAT3 pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Shi-Wei-Ru-Xiang pills (SW) as a tradition Tibetan medicine has been clinically proved effective in rheumatoid arthritis (RA) treatment. However, the underlying mechanism of SW remains unclear. AIM OF THE STUDY: This study aimed to investigate the anti-arthritic effect of SW and its possible mechanisms of action. MATERIALS AND METHODS: A CIA rat model in vivo, and IL-1ß-stimulated synoviocytes or chondrocytes and a co-culture system (IL-1ß-stimulated synoviocytes/chondrocytes) in vitro were used to evaluate the effects of SW on the treatment of RA. Arthritic score, paw swelling rate, hematoxylin-eosin (HE) staining, and Safranin-O-Fast green (S-O) staining were used to evaluate the anti-arthritic activity of SW in CIA rats. TUNEL assay or flow cytometry were performed to measure chondrocytes apoptosis in vivo and invitro. The effects of SW on the expression and production of pro-inflammatory cytokines were assessed by qRT-PCR and Elisa. The inhibitory effects of SW on the phosphorylation of p38, Erk1/2, and STAT3 were analyzed by Western blot. RESULTS: SW treatment significantly alleviated paw swelling, severity of arthritic and cartilage destruction in CIA rats. Moreover, SW decreased the expression of mRNAs of proinflammatory cytokines including TNF-α, IL-1ß and IL-6 in the synovium, suppressed the production of these pro-inflammatory cytokines in serum and hind paws, downregulated the protein expression of p-p38, p-Erk1/2 and p-STAT3, and protected the chondrocytes apoptosis in CIA rats. Consistent with the results in vivo, SW also inhibited the activation of MAPK and STAT3 pathways, suppressed the expression of pro-inflammatory cytokines in IL-1ß-stimulated synoviocytes, and attenuated chondrocytes apoptosis in IL-1ß-stimulated chondrocytes. In the co-culture system, SW pre-treatment in IL-1ß-stimulated synoviocytes exhibited inhibition of chondrocytes apoptosis, which was associated with attenuation of inflammation in synoviocytes. CONCLUSION: These results suggested that the underlying mechanisms by which SW exerts its anti-arthritis effect may be related to the reduction of proinflammatory cytokine levels, inhibition of p38, Erk1/2 and STAT3 phosphorylation, and attenuating of chondrocyte apoptosis.

The Current Developments in Medicinal Plant Genomics Enabled the Diversification of Secondary Metabolites' Biosynthesis.

Medicinal plants produce important substrates for their adaptation and defenses against environmental factors and, at the same time, are used for traditional medicine and industrial additives. Plants have relatively little in the way of secondary metabolites via biosynthesis. Recently, the whole-genome sequencing of medicinal plants and the identification of secondary metabolite production were revolutionized by the rapid development and cheap cost of sequencing technology. Advances in functional genomics, such as transcriptomics, proteomics, and metabolomics, pave the way for discoveries in secondary metabolites and related key genes. The multi-omics approaches can offer tremendous insight into the variety, distribution, and development of biosynthetic gene clusters (BGCs). Although many reviews have reported on the plant and medicinal plant genome, chemistry, and pharmacology, there is no review giving a comprehensive report about the medicinal plant genome and multi-omics approaches to study the biosynthesis pathway of secondary metabolites. Here, we introduce the medicinal plant genome and the application of multi-omics tools for identifying genes related to the biosynthesis pathway of secondary metabolites. Moreover, we explore comparative genomics and polyploidy for gene family analysis in medicinal plants. This study promotes medicinal plant genomics, which contributes to the biosynthesis and screening of plant substrates and plant-based drugs and prompts the research efficiency of traditional medicine.

Tibetan Medicine Shi-Wei-Gan-Ning-San Alleviates Carbon Tetrachloride-Induced Chronic Liver Injury by Inhibiting TGF-ß1 in Wistar Rats.

Background: Shi-Wei-Gan-Ning-San (SWGNS) is a classic Tibetan prescription, which has obvious clinical effects in the treatment of viral hepatitis, fatty liver, liver fibrosis, liver cirrhosis, liver cancer, and other liver injuries. However, animal studies and mechanism studies are still lacking. This study aimed to investigate its hepatoprotective efficacy and pharmacological mechanism in animal experiments. Methods: Chronic liver injury was induced by oral administration of carbon tetrachloride (CCl4) in Wistar rats for 13 weeks. SWGNS was administered orally to rats at doses of 235, 705, and 1410 mg/kg for 13 weeks. Blood samples were collected for biochemical, ELISA, and radioimmunoassay. Livers were harvested for H&E and immunohistochemical staining. The major constituents of SWGNS were analyzed by HPLC. In vitro experiments were used to explore the protective effect of Crocin on BRL-3A in the environment of H2O2. Results: SWGNS reversed weight loss is induced by CCl4. Serum assays showed that SWGNS reduced CCl4-induced alanine aminotransferase, aspartate aminotransferase, total bilirubin, and γ-glutamyltransferase levels and increased the total protein and albumin levels. Histopathological evaluation showed that SWGNS alleviated hepatic steatosis, fibrosis, and inflammation. Furthermore, SWNGS reduced CCl4-induced elevations of TGF-ß1, hyaluronic acid, laminin, and collagen IV in serum and reduced the high expression of α-SMA in tissues. Moreover, Crocin I and II are the main components of SWGNS. Crocin attenuated the damaging effects of H2O2 on BRL-3A. Conclusions: In conclusion, SWGNS alleviated CCl4-induced chronic liver injury by inhibiting the TGF-ß1 pathway. This plays an important role in promoting traditional Tibetan medicine in clinical practice.

Chromosome-level genome of Entada phaseoloides provides insights into genome evolution and biosynthesis of triterpenoid saponins.

As a medicinal herbal plant, Entada phaseoloides has high levels of secondary metabolites, particularly triterpenoid saponins, which are important resources for scientific research and medical applications. However, the lack of a reference genome for this genus has limited research on its evolution and utilization of its medicinal potential. In this study, we report a chromosome-scale genome assembly for E. phaseoloides using Illumina, Nanopore long reads and high-throughput chromosome conformation capture technology. The assembled reference genome is 456.18 Mb (scaffold N50 = 30.9 Mb; contig N50 = 6.34 Mb) with 95.71% of the sequences anchored onto 14 pseudochromosomes. E. phaseoloides was estimated to have diverged from the Leguminosae lineage at ~72.0 million years ago. With the integration of transcriptomic and metabolomic data, gene expression patterns and metabolite profiling of E. phaseoloides were determined in different tissues. The pattern of gene expression and metabolic profile of the kernel were distinct from those of other tissues. Furthermore, the evolution of certain gene families involved in the biosynthesis of triterpenoid saponins and terpenes was analysed and offers new insights into the formation of these two metabolites. Four CYP genes, one UGT gene and related transcription factors were identified as candidate genes contributing to regulation of triterpenoid saponin biosynthesis. As the first high-quality assembled reference genome in the genus Entada, it will not only provide new information for the evolutionary study of this genus and conservation biology of E. phaseoloides but also lay a foundation for the formation and utilization of secondary metabolites in medicinal plants.

Analgesic and neuroprotective effects of Baimai Ointment on diabetic peripheral neuropathy.

ETHNOPHARMACOLOGY RELEVANCE: Baimai (BM) ointment, a traditional Tibetan medicine, has been widely used to treat "white vein" disease, paralysis, hemiplegia and claudication caused by trauma, because of its great effects on muscle stretching and collateral activation. As one of the most terrible complications in diabetes patients, diabetes peripheral neuropathy (DPN) is mainly manifested as abnormal pain or numbness in extremities. However, whether BM ointment is a potential drug for DPN treatment is unclear. AIMS OF THE STUDY: The aim of this study was to investigate the therapeutic effects of BM on DPN in a high-fat diet/low-dose of streptozotocin induced type 2 diabetes rat model and explore underlying mechanisms. METHODS: The chemical components of BM were determined by high performance liquid chromatography (HPLC), and the possible targets and related pathways candidates involved in the effects of BM on DPN were predicted using network pharmacology methods. Next, the effects of different doses (1.5, 3.0 and 6.0 g/kg) of BM on physiological changes, pain behaviors, motor nerve conduction velocity (MNCV) in DPN rats were assessed and compared with placebo- and mecobalamine (Meco)-treated DPN controls. Then, the effects of BM on the expression of pain associated genes as well as the phosphorylation of PI3K/AKT and MAPKs pathways in DRG of DPN rats were examined. RESULTS: Through HPLC analysis, curcumin was identified as one of the primary contents of BM. The information from network pharmacology indicated a series of target candidates for BM including IL6, IL10, TNF, CCL2, CXCL12, EGF, VEGFA, BDNF, TGFß1 and TNF, as well as PI3K-AKT and MAPK signaling pathways. Topical treatment of BM significantly improved the hypersensitivity of mechanical and thermal pain, MNCV and the morphological changes and demyelination of sciatic nerve fibers, without affecting the body weight, serum metabolism or blood glucose. The up-regulated levels of neuropeptides Cgrp, Sst, Sp and chemokines Ccl2 and Ccl3 along with the abnormal expression of p-P38, p-ERK and p-AKT in the DRG of DPN rats were alleviated by BM application. CONCLUSION: BM ointment has great activities in relieving pain hypersensitivity, neuroprotecting peripheral nerves damage caused by DPN, which may be related to the inhibition of related neuropeptide (Cgrp, Sst, Sp) and chemokine (Ccl2, Ccl3) expression and the regulation of PI3K/AKT and MAPKs signaling pathways in DRG.

Comparison of Herbal Medicines Used for Women's Menstruation Diseases in Different Areas of the World.

Aims: This review aims to compare the use of herbal medicine used to treat women's menstruation and the prevalence of menstrual diseases in different regions, which reveal the use of herbal medicine globally and provide scientific guidance for improving women's health. Materials and Methods: The information available on herbal medicines for women between the years 2000 and 2021 was systematically collected via the library and electronic search systems such as Google Scholar, PubMed, ScienceDirect, and Web of Science as well as secondary resources including books and conference proceedings. Results: Totally, 571 ethnic medicines commonly used for women's menstruation health in Asia, Europe, Oceania, Africa, and America were accounted. Zingiber officinale Roscoe (Ginger), Ruta graveolens L. (Common rue), Angelica sinensis (Oliv.) Diels (Angelica sinensis), Foeniculum vulgare Mill (Fennel), Catharanthus roseus (L.) G. Don (Catharanthus roseus) and other medicines which have obvious advantages and long-term usage are utilized in the treatment of menstrual diseases. Family Asteraceae, Lamiaceae, Apiaceae, Fabaceae, and Zingiberaceae are the most common medicinal plant families used for such treatments. In many instances, the application of fresh parts of plants was observed because of the healers' belief regarding the higher efficiency of the medicine made from fresh plants. Edible plants are used in a wide range of countries. Conclusion: Women's menstruation health is directly related to their health condition. Traditional medicines of most ethnic groups have contributed to women's health care and treatment of gynecological diseases. Practitioners in this field have gained elaborate experience in treatments and medication, and assembled a large number of effective drugs and prescriptions. These experiences have also been inherited and developed by modern clinical application and scientific research. However, the basic research on these drugs is not sufficient, the knowledge of drug use has not been fully popularized, the advantages of drugs have not been fully utilized, and the guiding potential to modern drug research continues to be insufficient. As such, it is necessary to further promote and make a significant contribution to women's health.

Triterpene saponins from Guo-gang-long attenuate collagen-induced arthritis via regulating A20 and inhibiting MAPK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The stems of Entada phaseoloides (L.) Merr commonly named "Guo-gang-long", is a traditional Chinese folk medicine that has been used clinically in China for the treatment of arthritis. Our previous study described that triterpene saponins isolated from "Guo-gang-long" could inhibit the inflammatory response. However, the potential mechanism of "Guo-gang-long" on treatment of arthritis, and whether the triterpene saponins responsible for its anti-arthritic effect are unclear. AIM: To investigate the function and mechanisms of the triterpene saponins from E. phaseoloides (ES) in collagen-induced arthritis (CIA) rats. MATERIALS AND METHODS: The chemical components of ES were analyzed by HPLC. Anti-arthritic activity of ES was investigated in CIA rats, which was established by immunization with bovine type II collagen. Three doses of ES (25, 50 and 100 mg/kg) were administrated using oral gavage to CIA rats daily for 3 weeks. The anti-arthritic activity of ES was evaluated by clinical arthritis scoring, paw swelling and mechanical sensitivity, as well as histological changes in CIA rats. The impacts of ES on the regulation of the ubiquintin-editing enzyme A20 and MAPK signaling pathway, and production of pro-inflammatory cytokines in CIA rats were examined by Western blot, quantitative real-time PCR, ELISA, and immunohistochemical staining, respectively. RESULTS: ES treatment relieved the paw swelling, hyperalgesia and joint destruction, and prevented the progression of arthritis in CIA rats. Meanwhile, ES suppressed the excessive mRNA levels and protein expression of TNF-α and IL-17 in synovial tissues and hind paw joints, and reduced the production of IL-1ß, TNF-α and IL-17 in serum. Furthermore, ES up-regulated A20 and suppressed the phosphorylation of p38 and ERK1/2 in hind paw joints, as well as inhibiting the activation of spinal p38 in CIA rats. CONCLUSION: ES could relieve rheumatic symptoms and prevent the development of rheumatoid arthritis. The effects of ES may be mediated by reducing proinflammatory cytokine levels, up-regulating A20 expression, reducing p38 and ERK1/2 activation in periphery, and inhibiting of phospho-p38 in spinal cord.

Investigation on the function tropism of Tiaoqin and Kuqin (different specification of Scutellaria baicalensis) by comparing their curative effect on different febrile disease model.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis (S. baicalensis) is the root of S. baicalensis Georgi. In traditional Chinese medicine it is divided into Tiaoqin (TQ, 1-3 years old) and Kuqin (KQ, more than 3 years old). However, the differences in TQ and KQ efficacy and their exact mechanisms are still unclear. AIM OF THE STUDY: This study aimed to clarify the difference in the efficacy of TQ and KQ in relation to different fever types (damp heat and hyperpyrexia) by using rat models, as well as to determine the primary molecular mechanism. MATERIALS AND METHODS: This study compared the compositional content of TQ and KQ by UPLC-MS/MS. Then, rat models of hyperpyrexia (HP, LPS) and damp heat (DH, high-fat and high-sugar diet feeding + fumigation in artificial climate chamber + E. coli injection) were established and their clinical symptoms, blood biochemistry, histopathological sections, cell cytokines and protein expression were compared following treatment with TQ or KQ. Finally, the mechanisms underpinning the differences observed for TQ and KQ were determined by measuring the components of these treatments in different target organs. RESULTS: This study identified 31 compounds in the water extracts of both TQ and KQ, which differed significantly in their relative content. TQ and KQ showed different functional tropism in HP and DH model rats. Baicalin, wogonoside, oroxin A, baicalein, wogonin and oroxylin A appeared to be the basic functional components responsible for the functional tropism hypothesis, while the remaining compounds appeared to be the efficacy-oriented components. In addition, the difference in pharmacodynamics between TQ and KQ may be related to their absorption in vivo, which was consistent with the hypothesis of functional tropism proposed in this work. CONCLUSION: In this study we adopted TQ and KQ-different specifications of Scutellaria baicalensis with similar chemical components-as a case study to systematically reveal the functional tropism of Chinese herbal medicine (CHM). The results showed that TQ and KQ contain the basic functional components to enable the basic function of 'clearing heat', while the variation in compositional content may result in their different therapeutic effects. A greater understanding and utilisation of the functional tropism of CHM would enormously improve the accuracy and scientific basis for the application of CHM medication, as well as in promoting the multi-function mechanism of CHM and guiding new drug development of CHM.

Polycyclic polyprenylated acylphloroglucinols from Garcinia xanthochymus fruits exhibit antitumor effects through inhibition of the STAT3 signaling pathway.

The fruits of Garcinia xanthochymus can be eaten raw or processed into jams, preserves and vinegar. They provide not only vitamin and protein nutrients, but also pharmacologically active compounds, among which polycyclic polyprenylated acylphloroglucinols (PPAPs) are a major class. According to the literature, PPAPs exhibited good anti-cancer effects. This study investigated the antitumor effects and the underlying mechanism of S1 (the regioisomeric mixture of xanthochymol and guttiferone E) and S2 (the regioisomeric mixture of isoxanthochymol and cycloxanthochymol) isolated from the fruits of G. xanthochymus. In an H22 allograft mouse model, S1 and S2 could suppress the liver tumor growth and phosphorylation of STAT3. Computational modeling showed that S1 and S2 could form hydrogen bonds with the SH2 domain of STAT3. In HepG2 and MCF-7 cell lines, S1 and S2 downregulated the expression of p-STAT3Tyr705. Moreover, S1 and S2 inhibited the phosphorylation of JAK2 and Src, which are the upstream kinases of STAT3, and the expression of various STAT3-regulated genes, including anti-apoptotic (Bcl-XL, Mcl-1 and survivin), proliferative (cyclin D1) and angiogenic (VEGF) genes. As a result, S1 and S2 arrested the cell cycle and induced cell apoptosis, which were proved by the activation of cleaved caspase-3 and caspase-8. These results demonstrated that S1 and S2 from G. xanthochymus exhibited antitumor effects through the inactivation of STAT3, and could be promising candidates for cancer treatment.

Comparative transcriptome analysis of root, stem, and leaf tissues of Entada phaseoloides reveals potential genes involved in triterpenoid saponin biosynthesis.

BACKGROUND: Entada phaseoloides (L.) Merr. is an important traditional medicinal plant. The stem of Entada phaseoloides is popularly used as traditional medicine because of its significance in dispelling wind and dampness and remarkable anti-inflammatory activities. Triterpenoid saponins are the major bioactive compounds of Entada phaseoloides. However, genomic or transcriptomic technologies have not been used to study the triterpenoid saponin biosynthetic pathway in this plant. RESULTS: We performed comparative transcriptome analysis of the root, stem, and leaf tissues of Entada phaseoloides with three independent biological replicates and obtained a total of 53.26 Gb clean data and 116,910 unigenes, with an average N50 length of 1218 bp. Putative functions could be annotated to 42,191 unigenes (36.1%) based on BLASTx searches against the Non-redundant, Uniprot, KEGG, Pfam, GO, KEGG and COG databases. Most of the unigenes related to triterpenoid saponin backbone biosynthesis were specifically upregulated in the stem. A total of 26 cytochrome P450 and 17 uridine diphosphate glycosyltransferase candidate genes related to triterpenoid saponin biosynthesis were identified. The differential expressions of selected genes were further verified by qPT-PCR. CONCLUSIONS: The dataset reported here will facilitate the research about the functional genomics of triterpenoid saponin biosynthesis and genetic engineering of Entada phaseoloides.

Acylphloroglucinol and tocotrienol derivatives from the fruits of Garcinia paucinervis.

Three undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs) and three tocotrienols derivatives, named as paucinochymol A-F (1-3 and 10-12), together with six known PPAPs, were isolated from the fruits of Garcinia paucinervis. Their structures and absolute configurations were determined by extensive NMR analysis and electronic circular dichroism (ECD) calculation methods. Paucinochymol A (1) is the first compound of this type featuring a ω-isogeranyl with tetrahydrofuran unit at C-1. Paucinochymols D and E (4-5) belong to rare tocotrienol with one glorious macrocyclic and an ortho-quinone moiety, respectively. The antiproliferative and anti-inflammatory activities of all isolates were tested. Four PPAPs exhibited weak inhibitory activities against three human cancer cell lines (HepG2, T98, MCF-7) with IC50 values ranging from 10.0 to 16.0 µM. Paucinochymol D (10) displayed moderate inhibitory effects against nitric oxide (NO) production with the IC50 value of 19.8 µM.

Dandelion polyphenols protect against acetaminophen-induced hepatotoxicity in mice via activation of the Nrf-2/HO-1 pathway and inhibition of the JNK signaling pathway.

We investigated the liver protective activity of dandelion polyphenols (DP) against acetaminophen (APAP; Paracetamol)-induced hepatotoxicity. Mice were acclimated for 1 week and randomly divided into the following groups (n = 9 per group): Control, APAP, APAP + DP (100 mg·kg-1), APAP + DP (200 mg·kg-1), and APAP + DP (400 mg·kg-1) groups. Mice were pretreated with DP (100, 200, and 400 mg·kg-1) by oral gavage for 7 d before being treated with 350 mg·kg-1 APAP for 24 h to induced hepatotoxicity. Severe liver injury was observed, and hepatotoxicity was analyzed after 24 h by evaluation of biochemical markers, protein expressions levels, and liver histopathology. Pretreatment with DP was able to restore serum liver characteristics (aspartate transaminase, AST; alanine aminotransferase, ALT; alkaline phosphatase, AKP), improve redox imbalance (superoxide dismutase, SOD; glutathione, GSH; malondialdehyde, MDA), and decrease inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-1ß, IL-1ß). Pretreatment with DP also significantly inhibited the expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, DP pretreatment could inhibit the apoptosis of liver cells caused by APAP through up-regulation of Bcl-2 and down-regulation of Bax and caspase-9 protein. DP also down-regulated p-JNK protein expression levels to inhibit APAP-induced mitochondrial oxidative stress and up-regulated the expression of Nrf-2 and its target gene HO-1. The histopathological staining demonstrated that DP pretreatment could inhibit APAP-induced hepatocyte infiltration, congestion, and necrosis. Our results demonstrate that DP pretreatment could protect against APAP-induced hepatic injury by activating the Nrf-2/HO-1 pathway and inhibition of the intrinsic apoptosis pathway.

Corydalis edulis total alkaloids (CETA) ameliorates cognitive dysfunction in rat model of Alzheimer disease through regulation of the antioxidant stress and MAP2/NF-κB.

BACKGROUND: In recent years, the morbidity of Alzheimer's disease in the world has become more and more serious. Therefore, it is an important means to find new drugs for treating AD from traditional medicines. It was found that Corydalis edulis Maxim. has a significant effect in the treatment of Alzheimer's disease (AD) in traditional application. In this work, we evaluated the efficacy of Corydalis edulis Maxim. total alkaloids (CETA) in AD model rats. METHODS: In this work, CETA was prepared by alkali extraction and acid precipitation, 11 alkaloids were identified by UPLC-MS/MS from CETA. AD model rats induced with D-galactose (D-gal) for 7 weeks. In modeling, the different doses of CETA (5, 20 mg/kg/Day) were continuously administered. Firstly, the change of the cognitive function, behavior, brain tissue pathology, and the activity of ROS, MDA, SOD, IL-1ß, TNF-α and CAT in rat hippocampal homogenate was measurement. Finally, the protein expression of Aß, microtubule-associated protein 2 (MAP2) and nuclear factor (κBp65) in rat brain was measurement. RESULT: CETA was found to have the activity in regulating AD. Compared with the normal control group, the levels of SOD and CAT in the hippocampus of the AD model group were decreased, and the level of ROS, MDA, IL-1ß and TNF-α was increased. The protein expression of Aß, and NF-κB were increased, and MAP2 were decreased. After treatment by CETA, the levels of SOD and CAT in hippocampus of AD model rats was significantly increased, ROS, MDA, IL-1ß and TNF-α were significantly decreased. The protein expression of Aß, and NF-κB were decreased, and MAP2 were increased. CONCLUSION: CETA can improve the learning and memory ability in AD model. The mechanism may be achieved by regulating the oxidative stress and inflammatory of AD rats, inhibiting the protein expression levels of Aß, and NF-κB, and promote the protein expression the levels of MAP2. Among them, 5 mg/kg is more effective than 20 mg/kg of CETA. Therefore, the therapeutic potential of CETA has been confirmed by our research, which may be a valuable drug for the treatment of AD.

Novel application of neural network modelling for multicomponent herbal medicine optimization.

The conventional method for effective or toxic chemical substance identification of multicomponent herbal medicine is based on single component separation, which is time-consuming, labor intensive, inefficient, and neglects the interaction and integrity among the components; therefore, it is necessary to find an alternative routine to evaluate the components more efficiently and scientifically. In this study, sodium aescinate injection (SAI), obtained from different manufacturers and prepared as "components knockout" samples, was chosen as the case study. The chemical fingerprints of SAI were obtained by high-performance liquid chromatography to provide the chemical information. The effectiveness and irritation of each sample were evaluated using anti-inflammatory and irritation tests, and then "Gray correlation" analysis (GCA) was applied to rank the effectiveness and irritability of each component to provide a preliminary judgment for product optimization. The prediction model of the proportions of the expected components was constructed using the artificial neural network. The results of the GCA showed that the irritation sorting of each SAI component was in the order of B > A > G > J > I > H > D > F > E > C and the effectiveness sorting of SAI components was in the order of D > C > B > A > F > E > H > I > G > J; the predictive proportion of SAI was optimized by the BP neural network as A: B: C: D: E: F = 0.7526: 0.5005: 5.4565: 1.4149: 0.8113: 1.0642. This study provided a scientific, accurate, reliable, and efficient approach for the proportion optimization of multicomponent drugs, which has a good prospect of popularization and application in product upgrading and development of herbal medicine.

Qingpeng Ointment Ameliorates Inflammatory Responses and Dysregulation of Itch-Related Molecules for Its Antipruritic Effects in Experimental Allergic Contact Dermatitis.

The pathogenesis of itchy skin diseases including allergic contact dermatitis (ACD) is complicated and the treatment of chronic itch is a worldwide problem. One traditional Tibetan medicine, Qingpeng ointment (QP), has been used in treatment of ACD in China for years. In this study we used HPLC and LC/MS analysis, combined with a BATMAN-TCM platform, for detailed HPLC fingerprint analysis and network pharmacology of QP, and investigated the anti-inflammatory and antipruritic activities of QP on ACD induced by squaric acid dibutylester (SADBE) in mice. The BATMAN-TCM analysis provided information of effector molecules of the main ingredients of QP, and possible chronic dermatitis-associated molecules and cell signaling pathways by QP. In ACD mice, QP treatment suppressed the scratching behavior induced by SADBE in a dose-dependent manner and inhibited the production of Th1/2 cytokines in serum and spleen. Also, QP treatment reversed the upregulation of mRNAs levels of itch-related genes in the skin (TRPV4, TSLP, GRP, and MrgprA3) and DRGs (TRPV1, TRPA1, GRP, and MrgprA3). Furthermore, QP suppressed the phosphorylation of Erk and p38 in the skin. In all, our work indicated that QP can significantly attenuate the pathological alterations of Th1/2 cytokines and itch-related mediators, and inhibit the phosphorylation of MAPKs to treat the chronic itch.