Gold-Catalyzed Cascade Reaction of Yne-Enones with Iminooxindoles, Access to 3,2'-Pyrrolidinyl-Spirooxindole Derivatives.

Herein, a gold-catalyzed cascade reaction of yne-enones with iminooxindoles has been developed through a cascade cycloisomerization/(3 + 2) annulation process. This approach provides a straightforward and efficient route for the synthesis of functionalized 3,2'-pyrrolidinyl-spirooxindoles in high reactivity and broad substrate scope with excellent cis-selectivity. Moreover, the subsequent functionalization of furan units allows for the diverse synthesis of spirooxindole derivatives, which have demonstrated good antitumoral activity.

Gastrodinol derivatives and prenylated flavones from the flower branch of Gastrodia elata.

Based on the research progress and traditional usage with whole herbal of the TCM "Tianma", chemical studies herein on the flower branch of Gastrodia elata were carried out in-depth and got 13 compounds including the gastrodinols (1-4), the flavonoid morins (5-8, 11-12), together with the specialist mulberrofurans (9, 13) and gastrodiamide (10) for the first time from the species. The antibacterial and cholinesterase inhibitory activities were then evaluated and the results showed that compounds 5, 11, 12, 13 have good activity against anti-methicillin-resistant Staphylococcus aureus, and compounds 9, 13 had good acetylcholinesterase inhibitory activity. All these results provide new chemical composition for better understanding the traditional application of "Tianma" and for exploring new pharmacological ingredients.

Two new sesquiterpene glycosides from Dendrobium findleyanum.

One new ylangene-type sesquiterpene glycoside, findlayanoside C (1), and one new picrotoxane-type sesquiterpene glycoside, findlayanoside D (3), together with five known sesquiterpene glycosides, dendrofindlayanoside C (2), dendronobiloside B (4), dendronobiloside A (5), dendroside F (6) and dendromoniliside D (7), have been isolated from the stems of Dendrobium findleyanum. The structures of compounds 1 and 3 were elucidated by means of extensive spectroscopic analyses, and their absolute configuration were confirmed by electronic circular dichroism (ECD) calculations. Cytotoxic activity assays against SMMC-7721, A-549 and MCF-7 human cancer cell lines revealed IC50 values of 10.12, 12.32 and 14.13 µM for compound 1, and of 9.25, 13.16 and 16.26 µM for compound 2. This study enriches the anti-tumour sesquiterpenoids composition of D. findleyanum.

"MD" method for the precise analysis of the O-acetyl-mannan structure and disclosure of the role in the conformational stability of insulin.

Among the diversified glycan modifications, acylation is one of the most abundant. This modification could be responsible for many of the properties of glycans, such as structural stability and specificity for biological activity. To obtain better insight into the effects of acetylation of glycans on the structure and thermostability of insulin, it is critical to investigate glycans with a high degree of acetylation. An in-depth study of three functional glycans named acetyl-mannan from Dendrobium devonianum (DDAM) was conducted herein by efficient enzymatic depolymerization, and the effect of glycosidic bonds on acetylation modification sites was studied through a molecular dynamics (MD) method, as well as its positive effect on insulin secretion, glucose uptake, and the thermal stability of tertiary structures in vitro. Further study indicated that DDAMs play a hypoglycemic role by sparking the thermostability of the insulin conformation. The hypoglycemic activity displayed a positive correlation with the degree of acetylation in DDAMs. In this work, through the MD method, we confirmed the structure characteristics of DDAMs and provided accurate data support for the structure-activity relationship analysis. Thus, these findings demonstrated that DDAMs might be an exceptional leading compound for the stability of insulin drug.

Interaction mechanism between luteoloside and corn silk glycans and the synergistic role in hypoglycemic activity.

As the two most principal active substances in the corn silk, polysaccharides and flavonoids, the mechanism of interaction between them has been a topic of intense research. This study provides an in-depth investigation of the interaction mechanism between corn silk glycans and luteoloside (LUT) and the synergistic role that result from this interaction. The interaction mechanism was evaluated by isothermal titration calorimetry (ITC) and circular dichroism (CD), and the synergistic role was evaluated by the expression of glucose transporters (GLUT-1), insulin secretion and surface plasmon resonance (SPR). CD and ITC results indicated that the interaction between CSGs and LUT mainly driven by the Cotton effects, enthalpy and entropy-driven. This interaction precipitated the formation of complexes (CSGs/LUT complexes) between corn silk glycans (CSGs) with four different molecular weights and luteoloside (LUT). Furthermore, the CSGs and LUT play a synergistic role in glucose regulation through GLUT-1 expression and insulin secretion experiments, compared to single luteoloside group.

An in-depth investigation of molecular interaction in zeaxanthin/corn silk glycan complexes and its positive role in hypoglycemic activity.

Glycans in corn silk could interact with co-existing small molecules during its absorption, digestion, and biological process. In order to understand the exact mechanism of action of zeaxanthin, it is critical to investigate the biomolecular interactions, which were necessary to form a glycan-small molecule complex and yet produce the bioactive effect. So far, the in-depth study of these natural interactions has not been fully elucidated. Here, we probed that the molecular interaction between zeaxanthin (ZEA) and glycans from corn silk (CSGs) was driven by enthalpy. More importantly, it was the first time found that CSGs can bind to lipid-soluble ZEA could be binded with CSGs. It was the first report on the thermostability of insulin structure and natural glycans. This study should facilitate our understanding of the interaction between lipid soluble molecules and glycans, and provide a more comprehensive understanding of the nutrient base in food.

Target acquisition of anti-aging manno-oligosaccharide that triggers ECM process via TGF-ß/Smads-SIRT1 signalling pathway.

Glycans play a crucial role in a variety of physiological and pathological processes. In terms of skin, the sugar chain length, monosaccharide composition and structure of glycans change with age, and thus the changes in glycogens in skin cells are a potential biomarker of aging. The exogenous addition of structurally defined glycans is of great importance for delaying the skin aging process. Fortunately, a functional glycan named manno-oligosaccharide (DOMOS) from Dendrobium officinale was obtained herein by efficient enzymatic depolymerization and exerts anti-aging effects on human skin in vitro and in vivo together with human clinical studies. Further studies show that DOMOS exerts anti-aging effects by triggering the ECM process through a TGF-ß/Smad-SIRT1 signalling pathway. This is the first study to concentrate on the beneficial effects of glycan degradation by a highly specific method on skin aging and provides an all-new solution to the skin aging problem that people are most concerned about.

Two new cadinene-type sesquiterpene glycosides from Dendrobium findlayanum.

Two new and one known cadinene-type sesquiterpene glycosides, findlayanosides A-B (1-2) and dendronobiloside D (3), were isolated from the stems of Dendrobium findlayanum. This is the first report that cadinene-type sesquiterpene glycosides were isolated from D. findlayanum. The structures of compounds 1 and 2 were elucidated by extensive spectroscopic analyses, and their absolute configurations were confirmed by electronic circular dichroism (ECD) calculations. The obtained compounds were evaluated for their cytotoxicity against HL-60, SMMC-7721, A-549 and MCF-7 human cancer cells, and no obvious cytotoxic activity was observed at the concentration of 25 µΜ.

Modern interpretation of the traditional application of Shihu - A comprehensive review on phytochemistry and pharmacology progress of Dendrobium officinale.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine (TCM) "Shihu" has a long history of medicinal use in China from some species of Dendrobium. D. officinale is a major source of "Shihu" and is widely cultivated in south of China and listed separately as "Tiepi Shihu" by the Chinese Pharmacopoeia in now time. Traditionally, D. officinale has been widely used in daily health care and the treatment of diabetes and gastrointestinal diseases. AIM OF THIS REVIEW: In order to better develop and utilize D. officinale, we conducted this systematic review of previous studies, showed clear structure of all isolates from D. officinale together with pharmacological progress, hoping to provide references for further research and utilization. In addition, specific display of the chemical components and the research progress of related activities can help to better understand the traditional records and modern pharmaceutical applications of the plant medicine. MATERIALS AND METHODS: Information on phytochemistry and pharmacological studies of D. officinale was collected from various scientific databases including Web of Science, SciFinder, ACS, Springer, Scopus, PubMed, ScienceDirect, Google Scholar and CNKI. RESULTS: More than 180 compounds isolated from D. officinale, including bibenzyls, phenols, phenylpropanoids, lignans, flavonoids and polysaccharides are listed in this review. Furthermore, modern pharmacological researches such as hypoglycemia, immune regulation, antioxidant, cardiovascular regulation and gastrointestinal protection are summarized. CONCLUSION: Based on the summary of the research work of D. officinale, we systematically show the chemical composition of the plant, and concluded the relationship of those composition with plant habitat together with the relationship between the structure of chemical components and pharmacological activity. Moreover, we suggest that some of small molecule compounds could also be quality control of D. officinale besides polysaccharides.

The Extracts of Dendrobium Alleviate Dry Eye Disease in Rat Model by Regulating Aquaporin Expression and MAPKs/NF-κB Signalling.

Dry eye is one of the most common ocular surface diseases caused by tear film instability and ocular surface damage due to an abnormal quality or quantity of tears. Inflammatory factors can initiate relevant transduction signalling pathways and trigger the inflammatory cascade response, resulting in ocular surface inflammation. It has been shown that the active ingredients in Dendrobium, such as polysaccharides, alkaloids and phenols, have anti-inflammatory, anti-tumour and immunity-boosting effects, and Dendrobium officinale extract can improve glandular secretion function, increase salivary secretion and increase the expression level of water channel protein in salivary glands in patients with dry eye syndromes. We investigated the in vitro cytoprotective effect of Dendrobium extracts in sodium chloride induced hyperosmotic conditions in human cornea keratocytes (HKs). Results showed that Dendrobium officinale Kimura et Migo water extract (DOW) and Dendrobium loddigesii Rolfe water extract (DLW) could upregulate the expression of aquaporins (AQP)5 protein, thus exerting a repairing effect by promoting cell migration. Furthermore, oral administration of DOW and DLW enhanced tear production in rats and exerted a protective effect on ocular surface damage. DOW and DLW could upregulate the expression of AQP5 and mucin (muc)5ac proteins in the lacrimal gland and reduce the inflammatory response. DOW and DLW inhibited the activation of the corresponding mitogen-activated protein kinases (MAPK) and NF-KB pathway, thereby playing a role in improving dry eye symptoms. This study provides a new perspective on dry eye treatment, and DOW and DLW may be potential therapeutic agents for dry eye.

Rubia cordifolia L. ameliorates DSS-induced ulcerative colitis in mice through dual inhibition of NLRP3 inflammasome and IL-6/JAK2/STAT3 pathways.

The aerial part of â€‹Rubia cordifolia â€‹L. has been used as an herbal medicine for a long time with various pharmacological activities, including anti-inflammatory, anticancer, and antibacterial activities. The most notable usage of these was that this herbal medicine had good therapeutic effects on diarrhea caused by various factors. However, the mechanism for the ethanolic extract of â€‹R. cordifolia â€‹L. (RCEE) to treat Ulcerative colitis (UC) effectively is still unclear. In this study, DSS successfully induced UC mice and then intervene using different polar parts of RCEE. The results indicated that RCEE-treatment inhibited colonic combination NLRP3 inflammasome formation and IL-6/JAK2/STAT3 activation in vivo, significantly ameliorating the clinical symptoms, including alleviating colonic mucosal damage and infiltration of macrophages, suppressing the release of inflammatory cytokines, and reducing mortality. Taken together, this study suggests that dual inhibition of NLRP3 inflammasome and IL-6/JAK2/STAT3 pathways activation using RCEE may be a promising therapeutic strategy for preventing the progression of UC.

A new polysaccharide platform constructs self-adjuvant nanovaccines to enhance immune responses.

BACKGROUND: Nanovaccines have shown the promising potential in controlling and eradicating the threat of infectious diseases worldwide. There has been a great need in developing a versatile strategy to conveniently construct diverse types of nanovaccines and induce potent immune responses. To that end, it is critical for obtaining a potent self-adjuvant platform to assemble with different types of antigens into nanovaccines. RESULTS: In this study, we identified a new natural polysaccharide from the rhizomes of Bletilla striata (PRBS), and used this polysaccharide as a platform to construct diverse types of nanovaccines with potent self-adjuvant property. In the construction process of SARS-CoV-2 nanovaccine, PRBS molecules and RBD protein antigens were assembled into ~ 300 nm nanoparticles by hydrogen bond. For HIV nanovaccine, hydrophobic effect dominantly drove the co-assembly between PRBS molecules and Env expression plasmid into ~ 350 nm nanospheres. Importantly, PRBS can potently activate the behaviors and functions of multiple immune cells such as macrophages, B cells and dendritic cells. Depending on PRBS-mediated immune activation, these self-adjuvant nanovaccines can elicit significantly stronger antigen-specific antibody and cellular responses in vivo, in comparison with their corresponding traditional vaccine forms. Moreover, we also revealed the construction models of PRBS-based nanovaccines by analyzing multiple assembly parameters such as bond energy, bond length and interaction sites. CONCLUSIONS: PRBS, a newly-identified natural polysaccharide which can co-assemble with different types of antigens and activate multiple critical immune cells, has presented a great potential as a versatile platform to develop potent self-adjuvant nanovaccines.

Multifunctional Anti-Alzheimer's Disease Effects of Natural Xanthone Derivatives: A Primary Structure-Activity Evaluation.

Background: A series of α-Mangostin (α-M) derivatives were designed and synthesized. α-M and four analogues were evaluated for their multifunctional anti-Alzheimer's disease (anti-AD) effects on fibrillogenesis, microglial uptake, microglial degradation, and anti-neurotoxicity of Aß, as well as LPS-induced neuroinflammation. The differences in bioactivities were analyzed to understand the structure-activity relationship for further modifications. Purpose: This study aims to investigate the anti-AD effects of α-M and elucidate its structure-activity relationship by comparing difference between α-M and several analogues. Methods: Aß fibrillogenesis was detected by Thioflavin T fluorometric assay. The levels of Aß1-42 and inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay. Neuron viability was examined by the CCK-8 assay. The morphology of ZO-1 of bEnd.3 cultured in BV-2-conditioned medium was evaluated by immunofluorescence staining. Results: Aß fibrillogenesis was significantly inhibited by co-incubation with α-M, Zcbd-2 or Zcbd-3. α-M, Zcbd-2, Zcbd-3, and Zcbd-4 decreased the levels of Aß1-42 and inflammatory cytokines, and promoted Aß uptake, degradation and anti-inflammation effects inflammation in microglia. α-M and Zcbd-3 protected neuron viability from Aß-induced neurotoxicity, and preserved tight junction integrity of bEnd.3 against LPS-induced neuroinflammation. Conclusion: Zcbd-3 acted as α-M almost in all effects. The structure-activity analysis indicated that the 3-methyl-2-butenyl group at C-8 is essential for the bioactivity of α-M, while modifying the double hydroxylation at the C-2 position may improve the multifunctional anti-AD effects.

The structures of two glucomannans from Bletilla formosana and their protective effect on inflammation via inhibiting NF-κB pathway.

Bletilla formosana is a traditional Chinese herbal medicine and is widely consumed as foods and medicines in China. However, the chemical structure and bioactivity of its polysaccharides remain unknown. Herein, two new polysaccharides, BFP60 and BFP80, with molecular weights of 3.99 kDa and 10.07 kDa, respectively, were isolated and purified from dried tuber of B. formosana. Structural analysis suggested that BFP60 and BFP80 may have backbone consisted of →4)-ß-d-Man-(1→,→4)-ß-d-Glc-(1→,→4)-2-O-acetyl-ß-d-Man-(1→, and →4)-3-O-acetyl-ß-d-Man-(1→. Inflammation assay in LPS-induced RAW264.7 cells showed that the productions of NO and pro-inflammatory cytokines including IL-6, IL-1ß, TNF-α, and IFN-γ were significantly reduced, and the expression of iNOS, COX-2, and target proteins in the NF-κB pathway were suppressed after BFP60 and BFP80 pretreatment. These findings indicated that this novel polysaccharide had significant inflammatory protective effects in vitro.

Structural characterization and biological evaluation of a new O-acetyl-1,4-linked-ß-d-mannan possessed potential application in hydrophilic polymer materials from Dendrobium devonianum.

To explore the active polysaccharides from Dendrobium devonianum, a novel O-acetylmannan (DDP-1) with molecular weight of 117 kDa was isolated from D. devonianum. The chemical and instrumental analysis indicated that the DDP-1 was a homopolysaccharide containing a backbone chain composed of →4)-ß-d-Manp-(1 â†’ (71.4%) residue with internal →4)-2-O-acetyl-ß-d-Manp-(1 â†’ (14.2%), →4)-3-O-acetyl-ß-d-Manp-(1 â†’ (7.1%), and non-reducing end ß-d-Manp-(1 â†’ (7.3%) residues. Anticancer assay in vitro revealed that DDP-1 had anticancer activity against the growth of HepG2 and MCF-7 cancer cells. Moreover, cytokine secretion assays also presented that DDP-1 can promote cytokine production of TNF-α and IL-6 in THP-1 macrophage stimulated by PMA. Finally, the effects of isolation and purification on the microstructure of DDP-1 was studied by scanning electron microscope. The morphological features of DDP-1 indicated that DDP-1 hold high potential application in hydrophilic polymer materials.

Purification, structural characterization and immunomodulatory activities of a polysaccharide from the fruiting body of Morchella sextelata.

A novel polysaccharide (MSP-1) was isolated from the fruiting body of Morchella sextelata and purified using DEAE-52 and Sephadex G-75. The molecular weight of MSP-1 was 1.17 × 104 Da, as detected by HPLC analysis. The monosaccharide composition of MSP-1 was mannose and glucose at a ratio of 1.00: 1.25. Methylation and NMR results revealed that the backbone of MSP-1 was composed of →4)-ß-D-Manp-(1→, →4)-ß-D-Glcp-(1→, →4)-α-D-Glcp-(1→, and →4, 6)-α-D-Glcp-(1→. SEM images of MSP-1 presented a dense network structure with porous characterizations. The immunomodulatory activities of MSP-1 were evaluated using RAW264.7 cells, and the results showed that MSP-1 promoted proliferative and phagocytic activity and increased the production of NO, TNF-α and IL-6. These results indicated that MSP-1 exhibited significant immunomodulatory activities.

Anthraquinones from the Aerial Parts of Rubia cordifolia with Their NO Inhibitory and Antibacterial Activities.

The present study aimed to identify the composition of the aerial parts of Rubia cordifolia L. A chemical investigation on the EtOAc extracts from the aerial parts of Rubia cordifolia resulted in the isolation of four new anthraquinones, namely Cordifoquinone A-D (1-4), along with 16 known anthraquinones. Their structures were elucidated on the basis of NMR and HR-ESIMS data. All isolates were assessed for their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophage cells. Compounds 1, 3 and 10 exhibited significant inhibitory activities with IC50 values of 14.05, 23.48 and 29.23 µmol·L-1, respectively. Their antibacterial activities of four bacteria, Escherichia coli (ATCC 25922), Staphylococcus aureus subsp. aureus (ATCC 29213), Salmonella enterica subsp. enterica (ATCC 14028) and Pseudomonas aeruginosa (ATCC 27853), were also evaluated. Our results indicated that the antibacterial activity of these compounds is inactive.

The bibenzyl derivatives of Dendrobium officinale prevent UV-B irradiation induced photoaging via SIRT3.

Dendrobium officinale is a valuable medicinal herb that is widely used in traditional Chinese medicine. The chemical constituents of D. officinale have attracted much attention and a large number of compounds have been reported including many bibenzyl derivatives. 13 bibenzyl derivatives from D. officinale were sent for molecular docking, surface plasmon resonance (SPR) assay and after detection of Mn-SOD and SIRT3 activities in or not in HaCaT cells, it was concluded that bibenzyl derivatives did not directly activate Mn-SOD but promoted SIRT3 proteins. In addition, HaCaT cells were irradiated with UV-B to induce an oxidative stress model in vitro to further verify the effect of bibenzyl derivatives. The results show that bibenzyl derivatives could directly bind to SIRT3, enhance the deacetylation and then activate Mn-SOD, so as to protect UV-B induced skin photoaging.

Target-Based Virtual Screening and LC/MS-Guided Isolation Procedure for Identifying Phloroglucinol-Terpenoid Inhibitors of SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 5 million deaths worldwide to date. Due to the limited therapeutic options so far available, target-based virtual screening with LC/MS support was applied to identify the novel and high-content compounds 1-4 with inhibitory effects on SARS-CoV-2 in Vero E6 cells from the plant Dryopteris wallichiana. These compounds were also evaluated against SARS-CoV-2 in Calu-3 cells and showed unambiguous inhibitory activity. The inhibition assay of targets showed that compounds 3 and 4 mainly inhibited SARS-CoV-2 3CLpro, with effective Kd values. Through docking and molecular dynamics modeling, the binding site is described, providing a comprehensive understanding of 3CLpro and interactions for 3, including hydrogen bonds, hydrophobic bonds, and the spatial occupation of the B ring. Compounds 3 and 4 represent new, potential lead compounds for the development of anti-SARS-CoV-2 drugs. This study has led to the development of a target-based virtual screening method for exploring the potency of natural products and for identifying natural bioactive compounds for possible COVID-19 treatment.

Ten picrotoxane-type sesquiterpenoids from the stems of Dendrobium wardianum Warner.

Ten undescribed picrotoxane-type sesquiterpenoids, dendrowardins A-J, together with two known ones, were isolated from the stems of Dendrobium wardianum Warner (Orchidaceae). Dendrowardins A-D feature the unusual 5,2-δ-lactone and additionally dendrowardins C-D are the first examples containing the 11,10-γ-lactone moiety. The structures were established using spectroscopic methods and by comparison with literature data. Further, dendrowardin E, amotin, and aduncin exhibited significant effects of promoting the proliferation on human lens epithelial cells (HLECs) induced by D-galactose.