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Twenty-one new iridoids, jatamansidoids A-U (1-12, 21-26, 32, 35 and 36), two new natural ones, jatamansidoids V (37) and W (38), eighteen known ones (13-20, 27-31, 33 and 34), together with three patchoulol-type sesquiterpenoids (39-41), were isolated from the roots and rhizomes of Valeriana jatamansi. Structurally, compounds 1-7 were the first examples of iridoids from V. jatamansi with unique α, β, γ, δ-unsaturated aldehyde fragment between C-11, C-4, C-5, C-9 and C-8; compound 8 was an unprecedented iridoid derivative with a methyl group (Me-10) at C-1, rather than C-8, and its plausible biogenetic pathway was proposed in this paper; compounds 22 and 23 were the first examples of Δ 4(5) -iridoids simultaneously replaced by oxygen-containing groups at C-3, C-6 and C-7; compound 24 was the first iridoid with both 6,7- and 1,10-epoxy fragments. The structures and absolute configurations of new compounds were elucidated based on extensive spectroscopic techniques and quantum chemical calculation. Furthermore, compounds 13-15 and 39-41 exhibited potent anti-influenza virus activities with H1N1 and H3N2 strains, with IC 50 values of 0.21-1.48 µM., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Genipin is an important monoterpene iridoid compound isolated from Gardenia jasminoides J.Ellis fruits and from Genipa americana fruits, or genipap. It is a precursor of a blue pigment which may be attractive alternative to existing food dyes and it possesses various potential therapeutic properties such as anti-cancer, anti-diabetic and hepatoprotective activity. Biomedical studies also show that genipin may act as a neuroprotective drug. This review describes new aspects of the bioactivity of genipin against various diseases, as well as its toxicity and industrial applications, and presents its potential mechanism of action.

Objectives: Spinal cord injury (SCI) is a disastrous central nervous system (CNS) disorder, which was intimately associated with oxidative stress. Studies have confirmed that Iridoids Effective Fraction of Valeriana jatamansi Jones (IEFV) can scavenge reactive oxygen species. This study aimed to confirm the efficacy of IEFV in ameliorating SCI., Methods: For establish the SCI model, the Sprague-Dawley rats underwent a T10 laminectomy with transient violent oppression by aneurysm clip. Then, the rats received IEFV intragastrically for 8 consecutive weeks to evaluate the protective effect of IEFV on motor function, oxidative stress, inflammation and neurotrophic factors in SCI rats., Results: Basso, Beattie and Bresnahan scores, hematoxylin and eosin (H&E) staining and transmission electron microscopy experiments found IEFV protected motor function and alleviated neuron damage. Meanwhile, IEFV treatment decreased the release of malondialdehyde, interleukin-6 (IL-6), cyclooxygenase-2 and tumor necrosis factor-α. Moreover, IEFV treatment elevated the expression levels of brain-derived neurotrophic factor and nerve growth factor of SCI rats. Finally, administration of IEFV significantly inhibited the expression of p-p65 and toll-like receptor 4 (TLR4)., Conclusions: This study suggests that IEFV could attenuate the oxidative stress and inflammatory response of the spinal cord after SCI, which was associated with inhibition of the TLR4/nuclear factor-kappaB signaling pathway., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patrinia scabra Bunge is a well-known herbal medicine for its favorable treatment on inflammatory diseases owing to its effective ingredients, in which iridoid glycoside plays an extremely significant role. This article aimed to improve the content of total iridoid glycosides in crude extract through a series optimization of extraction procedure. Moreover, considering that both pain and inflammation are two correlated responses triggered in response to injury, irritants or pathogen, the article investigated the anti-inflammatory and analgesic activities of P. scabra to screen out the active fraction., Method: P. scabra was extracted by ultrasonic-microwave synergistic extraction (UMSE) to obtain total iridoid glycosides (PSI), during which a series of conditions were investigated based on single-factor experiments. The extraction process was further optimized by a reliable statistical method of response surface methodology (RSM). The elution fractions of P. scabra extract were prepared by macroporous resin column chromatography. Through the various animal experiment including acetic acid-induced writhing test, formalin induced licking and flinching, carrageenan-induced mice paw oedema test and xylene-induced ear edema in mice, the active fractions with favorable analgesic and anti-inflammatory effect were reasonably screen out., Results: The content of PSI could reach up to 81.42 ± 0.31 mg/g under the optimum conditions as follows: ethanol concentration of 52%, material-to-liquid ratio of 1:18 g/mL, microwave power at 610 W and extraction time of 45 min. After gradient elution by the macroporous resin, the content of PSI increased significantly. Compared with other concentrations of elution liquid, the content of PSI in 30 and 50% ethanol eluate was increased to reach 497.65 and 506.90 mg/g, respectively. Owing to the pharmacology experiment, it was reasonably revealed that 30 and 50% ethanol elution fractions of P. scabra could relieve pain centrally and peripherally, exhibiting good analgesic and anti-inflammatory activities., Conclusion: Patrinia scabra possessed rich iridoids and exhibited significant analgesic and anti-inflammatory activities., (© 2022. The Author(s).)

Background: Asperulosidic acid (ASP) is a bioactive iridoid exerting broad pharmacological and medicinal properties. However, it is still unknown if ASP has therapeutical effects on gestational diabetes mellitus (GDM). This study aims to evaluate the effects of ASP on GDM as well as its underlying mechanism., Methods: A mouse model of GDM was established and orally administrated ASP (10, 20, and 40 mg/kg) on gestation day (GD) 0. The mice were sacrificed on GD 18., Results: Blood glucose and serum insulin were then determined. The inflammatory cytokines including IL-6 and TNF-α and oxidative stress biomarkers including MDA, SOD, GSH, and GPx were determined by using specific ELISAs. In addition, the expressions of NF-κB and MAPK signaling pathway-related proteins were determined by using Western blotting. Treatment with ASP decreased blood glucose in the mouse model of GDM. Besides, ASP also increased serum insulin and attenuated β-cell function. Treatment with ASP suppressed IL-6 and TNF-α and regulated oxidative stress-related biomarkers. Western blotting analysis showed that treatment with ASP suppressed phosphorylation of NF-κB p65, ERK1/2, and p38 in placental tissues., Conclusion: ASP alleviates placental oxidative stress and inflammatory responses in GDM by the inhibition of the NF-κB and MAPK signaling pathways., (© 2022 S. Karger AG, Basel.)

Improving autophagy-lysosome fusion has been considered a key method in the treatment of Alzheimer's disease (AD). Cornel iridoid glycoside (CIG) is extracted from Cornus officinalis and has been shown to promote the clearance of tau oligomers via the autophagy pathway. However, the mechanisms of CIG on autophagy deficits are not understood. Here, we found autophagy deficit and tau aggregation in the brains of P301S tau transgenic mice and MAPT cells edited using CRISPR-Cas9 technology. CIG decreased tau aggregation and alleviated autophagic markers involving the JNK/Beclin-1 signaling pathway which demonstrated CIG that might enhance lysosome formation by upregulating ATPase Vps4A expression. Knocking down VPS4A increased autophagosome accumulation and attenuated the effect of CIG on p62. In addition, CIG had no effect on tau oligomers but still inhibited the level of tau monomer in VPS4A knockout cells. The effective component (Sweroside, SWE) of CIG attenuated tau oligomers accumulation and increased Vps4A level but not CHMP2B. SWE could not change the level of tau oligomers in VPS4A knockout cells. In conclusion, CIG suppressed autophagosome accumulation by regulating the ATPase Vps4A/JNK. SWE is a core of active factors of CIG in Vps4A regulation. These findings suggest CIG may be a potential drug in AD treatment.

Oleuropein is an ester of elenolic acid and hydroxytyrosol (3, 4-dihydroxyphenylethanol). It is a phenolic compound and the most luxuriant in olives. The detailed information related to the anticancer effects of oleuropein was collected from the internet database PubMed/Medline, ResearchGate, Web of Science, Wiley Online Library, and Cnki using appropriate keywords until the end of October 2021. Oleuropein has been shown to have antioxidant, anticancer, antiinflammatory, cardioprotective, neuroprotective, and hepatoprotective effects. Previous studies also revealed that oleuropein could effectively inhibit the malignant progression of esophageal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, and cervical cancer. Recently, the role of oleuropein in inhibiting tumor cell proliferation, invasion, and migration and inducing tumor cell apoptosis has gained extensive attention. In this review, we have summarized the latest research progress related to the antioncogenic mechanisms and the potential role of oleuropein in targeting different human malignancies. Based on these findings, it can be concluded that oleuropein can function as a promising chemopreventive and chemotherapeutic agent against cancer, but its more detailed anticancer effects and underlying mechanisms need to be further validated in future preclinical as well as clinical studies., (© 2021 John Wiley & Sons Ltd.)

Mounting evidence has shown that single-targeted therapy might be inadequate to achieve satisfactory effects. Thus, drug combinations are gaining attention as they can regulate multiple targets to obtain more beneficial effects. Heat shock protein 90 (HSP90) is a molecular chaperone that assists the protein assembly and folding of client proteins and maintains their stability. Interfering with the interaction between HSP90 and its client proteins by inhibiting the latter's activity may offer a new approach toward combination therapy. The HSP90 client protein AKT plays an important role in the inflammatory response syndrome caused by infections. In this study, the dietary flavone baicalein was identified as a novel inhibitor of HSP90 that targeted the N-terminal ATP binding pocket of HSP90 and hindered the chaperone cycle, resulting in AKT degradation. Combining baicalein with genipin, which was extracted from Gardenia jasminoides , could inhibit the pleckstrin homology domain of AKT, significantly increasing the anti-inflammatory effects both in vitro and in vivo. This synergistic effect was attributed to the reduction in AKT expression and phosphorylation. Thus, elucidating the mechanism underlying this effect will provide a new avenue for the clinical application and development of synergistic anti-inflammatory drugs.

Geniposide (GEN) is a natural antioxidant and anti-inflammatory product and plays an important role in the treatment of diabetes and diabetic complications. To explore the biological functions and mechanism of GEN in diabetic retinopathy (DR), we constructed the in vitro and in vivo model of DR by using primary cultured mouse retinal Müller cells and C57BL/6 mice, respectively. We found that GEN inhibited ROS accumulation, NF- κ B activation, Müller cell activation, and inflammatory cytokine secretion both in vitro and in vivo, which is probably mediated through the Nrf2 pathway. Exendin (9-39) (EX-9), an antagonist of glucagon-like peptide-1 receptor (GLP-1R), abolished the protective effect of GEN on high glucose- (HG-) induced Müller cells. Additionally, GEN decreased hyperglycemia-induced damage to Müller cells and blood-retinal barrier in the retinas of mice with DR. We demonstrated that GEN was capable of protecting Müller cells and mice from HG-induced oxidative stress and inflammation, which is mostly dependent on the Nrf2 signaling pathway through GLP-1R. GEN may be an effective approach for the treatment of DR., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2021 Yuanyuan Tu et al.)

Background: Overexposure to glucocorticoid (GC) produces various clinical complications, including osteoporosis (OP), dyslipidemia, and hypercholesterolemia. Geniposide (GEN) is a natural iridoid compound isolated from Eucommia ulmoides. Our previous study found that GEN could alleviate dexamethasone (DEX)-induced differentiation inhibition of MC3T3-E1 cells. However, whether GEN protected against Dex-induced cholesterol accumulation in osteoblasts was still unclear., Methods: DEX was used to induce rat OP. Micro-CT data was obtained. The ALP activity and mineralization were determined by the staining assays, and the total intracellular cholesterol was determined by the ELISA kits. The protein expression was detected by western blot., Results: GEN ameliorated Dex-induced micro-structure damages and cell differentiation inhibition in the bone trabecula in rats. In MC3T3-E1 cells, Dex enhanced the total intracellular cholesterol, which reduced the activity of cell proliferation and differentiation. Effectively, GEN decreased DEX-induced cholesterol accumulation, enhanced cell differentiation, and upregulated the expression of the GLP-1R/ABCA1 axis. In addition, inhibition of ABAC1 expression reversed the actions of GEN. Treatment with Exendin9-39, a GLP-1R inhibitor, could abrogate the protective activity of GEN., Conclusions: GEN ameliorated Dex-induced accumulation of cholesterol and inhibition of cell differentiation by mediating the GLP-1R/ABCA1 axis in MC3T3-E1 cells.

Ethnopharmacological Relevance: Loganin, an iridoid glycoside, is one of the quality control indexes of Cornus officinalis Sieb. et Zucc. Increasing evidence emphasize the important role of inflammation in the pathology of depression, which links depression with other chronic diseases. Loganin prevents inflammatory response in multiple diseases and reverses depressive-like behaviors. However, the mechanisms underlying antidepressant-like effects of loganin for the treatment of inflammation-associated depression are not utterly understood., Aim of the Study: The present study was designed to predict the potential targets of loganin against inflammation-associated depression using a network pharmacology approach., Materials and Methods: Pharmmapper and Uniport were used to predict loganin-related targets. Targets of inflammation were identified through GeneCards databases and Online Mendelian Inheritance in Man (OMIM). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to identify the potential mechanism. Finally, qRT-PCR and ELISA were used to confirm the role of loganin on these targets., Results: There were 15 nodes in the loganin-inflammation-depression intersection targets network. In the network, the degree value of CTNNB1 was above 3. Among top ten pathways identified by KEGG analysis, Th1/Th2 cell differentiation and IL-17 signaling pathways were related with both inflammation and depression. As indicated by qRT-PCR results, loganin increased CTNNB1 mRNA level. Moreover, loganin elevated M2 markers of microglia but decreased M1 markers of microglia against lipopolysaccharide (LPS), indicated by qRT-PCR results and ELISA results., Conclusion: CTNNB1 was the main target of loganin. Loganin alleviated LPS-induced inflammation through inhibiting M1 polarization of microglia. Our results provide a better understanding of loganin-induced antidepressant-like effects for the treatment of inflammation-associated depression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Context: Valeriana jatamansi Jones [syn. V. wallichii DC, (Valerianaceae)] (VJJ) is used to treat depression., Objective: To explore the effects of total iridoids of VJJ extract (TIV) on chronic unpredictable mild stress (CUMS) in mice., Materials and Methods: VJJ roots and rhizomes were extracted with 70% ethanol. CUMS rats were treated daily with fluoxetine (2.6 mg/kg, i.g.) or TIV (5.7, 11.4, and 22.8 mg/kg, i.g.) for 14 days. Male Kun Ming mice on normal chow and 0.5% CMC-Na solution were used as a control. Behavioural tests included the tail suspension (TST) and sucrose preference tests (SPT). Evans blue staining was used to evaluate blood-brain barrier (BBB) permeability. Western blotting was used to measure zonula occludens-1 (ZO-1) and occludin expression. 16S rRNA sequencing was used to analyse intestinal flora abundance. Tax4Fun was used to predict KEGG metabolic pathways., Results: TIV treatment reduced TST time (117.35 ± 8.23 or 108.95 ± 6.76 vs. 144.45 ± 10.30 s), increased SPT (55.83 ± 7.24 or 53.12 ± 13.85 vs. 38.98 ± 5.43%), increased the abundance of phylum Firmicutes (86.99 ± 0.03 vs. 60.88 ± 0.19%) and genus Lactobacillus (75.20 ± 0.19 vs. 62.10 ± 0.13%), reduced the abundance of phylum Bacteroidetes (6.69 ± 0.06 or 11.50 ± 0.09 vs. 25.07 ± 0.20%). TIV increased carbohydrate metabolism (14.50 ± 3.00 × 10 -3 or 14.60 ± 2.00 × 10 -3 or 14.90 ± 2.00 × 10 -3 vs.13.80 ± 4.00 × 10 -3 %), replication and repair functions (5.60 ± 1.00 × 10 -3 or 5.60 ± 1.00 × 10 -3 vs. 5.10 ± 4.00 × 10 -3 %), reduced the frequency of infectious disease (1.60 ± 2.00 × 10 -4 or 1.90 ± 5.00 × 10 -4 or 1.80 ± 3.00 × 10 -4 vs. 2.20 ± 7.00 × 10 -3 %), BBB permeability (0.77 ± 0.30 vs. 1.81 ± 0.33 μg/g), and up-regulated the expression of ZO-1 (1.42-fold, 1.60-fold, 1.71-fold) and occludin (1.79-fold, 2.20-fold)., Conclusions: TIV may modulate the intestinal flora, thereby inducing the expression of ZO-1 and occludin, protecting the BBB and exerting an antidepressant effect.

Geniposide has been widely found to ameliorate many metabolic diseases. The recruitment and activation of brown/beige adipocytes are effective and promising methods for counteracting obesity and related diseases. However, the effect of geniposide on thermogenesis of adipocytes and its underlying mechanism have not yet been investigated. Here, we demonstrate that geniposide (25 mg/kg) reduces body temperature and cold tolerance of mice via suppressing thermogenic genes in interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT). Consistently, geniposide (20 mg/mL) suppresses thermogenic capacity of adipocytes (brown adipocytes and 3T3L1 preadipocyte cells) in vitro. Mechanistically, geniposide reduces the level of protein kinase A (PKA) catalytic subunit and further suppresses transcription activity and protein stability of uncoupling protein 1 (UCP1), leading to reduction of thermogenic capacity in adipocytes. Moreover, pharmacological PKA activation reverses geniposide-induced UCP1 inhibition, which indicated that geniposide suppresses thermogenesis of adipocytes via regulating PKA signaling. Together, our findings suggest that geniposide is an inhibitor of fat thermogenesis, establishing a novel function characteristic of geniposide., (Copyright © 2021. Published by Elsevier B.V.)

Cornusdiridoid A-F (1-6), six unusual cornuside-morroniside secoiridoid dimers, and their possible new biogenetic precursor, 3″,5″-dehydroxycornuside (7), together with four known secoiridoids (8-11), were obtained from the fruits of Cornus officinalis. Their structures were elucidated on the basis of various spectroscopic and chemical methods. A plausible biosynthetic pathway of compounds 1-11 was proposed. The α-glucosidase inhibitory, antioxidant and anti-inflammatory activities of these isolates were evaluated. Some of them emerged out as potent antidiabetic, anti-inflammatory and free radical scavenging agents. Molecular docking was also carried out for antidiabetic target α-glucosidase to investigate the possible binding modes of the most potent α-glucosidase inhibitor, vincosamide (9). These results revealed that the secoiridoids from C. officinalis fruits may be served as new potential antidiabetic agents to prevent and treat type 2 diabetes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Full thickness cutaneous wound therapy and regeneration remains a critical challenge in clinical therapeutics. Recent reports have suggested that mesenchymal stem cells exosomes therapy is a promising technology with great potential to efficiently promote tissue regeneration. Multifunctional hydrogel composed of both synthetic materials and natural materials is an effective carrier for exosomes loading. Herein, we constructed a biodegradable, dual-sensitive hydrogel encapsulated human umbilical cord-mesenchymal stem cells (hUCMSCs) derived exosomes to facilitate wound healing and skin regeneration process. The materials characterization, exosomes identification, and in vivo full-thickness cutaneous wound healing effect of the hydrogels were performed and evaluated. The in vivo results demonstrated the exosomes loaded hydrogel had significantly improved wound closure, re-epithelialization rates, collagen deposition in the wound sites. More skin appendages were observed in exosomes loaded hydrogel treated wound, indicating the potential to achieve complete skin regeneration. This study provides a new access for complete cutaneous wound regeneration via a genipin crosslinked dual-sensitive hydrogel loading hUCMSCs derived exosomes.

The stems of Nauclea officinalis have been utilized as a crude drug in China, so other parts of the plant are abandoned, resulting in a waste of traditional Chinese medicine resources. To determine the distribution and content of the alkaloids, phenolic acids and iridoid in different organs (stem, branch, leaf and bark) of this plant, a reliable method has been established using LC-MS/MS. Nine constituents, namely strictosamide, vincosamide, chlorogenic acid, sweroside, naucleamide B, protocatechuic acid, pumiloside, vanillic acid and cryptochlorogenic acid, were simultaneously determined in 6 min. Meanwhile, the antipyretic, anti-inflammatory and analgesic activities were evaluated for comparative analysis of the pharmacological activity of different parts of N. officinalis. The results showed that the content of active components in other organs of N. officinalis was higher than that in stems, and the pharmacological effects of branches and leaves were also better. The established approach could be helpful for the quality control of N. officinalis, and also provide necessary information for the rational utilization of resources., (© 2021 John Wiley & Sons, Ltd.)

Extra-virgin olive oil (EVOO) is a critical component of the Mediterranean diet, which has been found beneficial to human health. Bitterness is often positively associated with the presence of phenolic compounds in EVOO. There are twenty-five bitter taste receptors (TAS2Rs) in humans, each of which responds to specific bitter tastants. The identity of phenolic compounds and the bitter taste receptors they stimulate remain unknown. In this study, we isolated 12 phenolic and secoiridoid compounds from the olive fruit and the oil extracted from it, and tested their ability to stimulate bitter taste receptor activity, using a calcium mobilization functional assay. Our results showed that seven out of twelve studied compounds activated TAS2R8, and five of them activated TAS2R1, TAS2R8, and TAS2R14. The phenolic compounds oleuropein aglycon and ligstroside aglycon were the most potent bitter tastants in olive oil. TAS2R1 and TAS2R8 were the major bitter taste receptors activated most potently by these phenolic compounds. The results obtained here could be utilized to predict and control the bitterness of olive oil based on the concentration of specific bitter phenolics produced during the milling process of olives., (© 2021. The Author(s).)

Zhi-zi-Hou-po decoction (ZZHPD) has been used to treat depression in the clinic for thousand years in China. However, the pharmacodynamic substance of ZZHPD is still not totally clear due to its complex components. The objective of this study was to identify the effectual combination ingredients (ECIs) of ZZHPD, which could represent the antidepressant effect of the original formula. Firstly, differential plasma absorbed components with different variable importance in projection (VIP) value in chronic unpredictable mild stress (CUMS)-induced depression and control rat were revealed by untargeted metabolomics-driven strategy based on HPLC-ESI-TOF/MS, XCMS online and SIMCA-p software. Secondly, network topology scores (NTS) of plasma absorbed components were exposed by protein-protein interaction (PPI) network analysis based on components-related genes and depression-related genes, which were performed by network pharmacology tools. Finally, the ECIs were screened by considered of VIP value and NTS. Then the bioactivity was evaluated by cell viability and expression of glial fibrillary acid protein (GFAP), tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) of a lipopolysaccharide-induced astrocyte depression model. An effective combination composed with 12 components was filtrated as ECIs of ZZHPD, exposed to which the cell viability effect, the expression of GFAP and IL-1β in astrocytes were essentially equivalent with original ZZHPD (p > 0.05), and that both characteristic constituents and trace compounds of ZZHPD might exert synergistic actions through multi-targets. The result of this study provided useful information for the clinical application and modern development of ZZHPD, and the proposed strategy could be regard as an alternative solution for effective combination screening of herbal medicines., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Spinal cord injury (SCI) is a traumatic condition of the central nervous system , which can cause nerve injury and affect nerve regeneration, thus leading to severe dysfunction of motor and sensory pathways, and unfortunately these effects are irreversible. Inflammatory response constitutes one of the important mechanisms of spinal cord secondary injury. Geniposide (Gen) is reported to possess anti-inflammation and neuronal repair capacities., Objectives: To investigate the effect and mechanism of Gen on motor function and inflammatory response in SCI rats., Methods: Sprague-Dawley (SD) rats were randomly grouped, and the SCI model was established by Allen's method. The motor function of rats was evaluated by the Basso, Beattie, and Bresnahan (BBB) scale. The protective effect of Gen on the injured spinal cord tissues was evaluated by measuring the water content, myeloperoxidase (MPO) activity, and levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6. Moreover, the protein level of the inflammation-related pathway was detected by spectrometry and Western blot assays., Results: Gen significantly promoted the recovery of SCI rats, decreased the edema of spinal cord tissues, reduced the area of cavity, increased the number of NF-200-positive neurons, as well as increased the number of horseradish peroxidase (HRP) retrograde tracing-positive neurons and regenerated axons with myelin sheath. Additionally, compared with the control group, the neutrophil infiltration, contents of TNF-α, IL-1β, and IL-6, the activity of inhibitor of nuclear factor κB kinase subunit β (IKKβ) kinase, and protein levels of (nuclear factor κB) NF-κB p65 and phosphorylated inhibitor of NF-κB (p-I-κB) in the Gen experimental group were significantly decreased., Conclusion: Gen effectively alleviated inflammatory response after SCI by inhibiting the IKKs/NF-κB signaling pathway and promoted the recovery of motor function and axon regeneration in rats., Significance: This study can provide novel insights for the early and effective intervention of SCI and confer basic data for the treatment of spinal cord secondary injury., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hyperuricemia is a principal factor mediating gout and kidney damage, and xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed and synthesized, and antihyperuricemic and nephroprotective effects of all derivatives was evaluated in vitro and in vivo. Compound 2e emerged as the most potent XOD inhibitor, with an IC 50 value of 6.67 ± 0.46 µM. Simultaneously, cell viability, ROS generation, and SOD levels assay showed that compound 2e could repair the damage of HKC cells by inhibiting the oxidative stress response. The results of the study indicated compound 2e significantly decreased uric acid levels by inhibiting the XOD activity, and repaired kidney damage by inhibiting the expression of TLR4/TLR2/MyD88/NF-κB and NALP3/ASC/caspase-1 signaling pathways. Enzyme inhibition kinetics suggested that compound 2e functioned via reversible mixed competitive inhibition. Moreover, a molecular docking study was performed to gain insight into the binding mode of compound 2e with XOD. These results suggest that geniposide derivatives were potential to be developed into a novel medicine to reveal healthy benefits in natural prevention and reduction risk of hyperuricemia and kidney damage., (Copyright © 2021 Elsevier Inc. All rights reserved.)

One new iridoid glycoside ( 1 ), shanzhiside N -L-phenylalanyl ester along with seven known compounds, mussaenoside ( 2 ), shanzhiside methyl ester ( 3 ), barlerin ( 4 ), mussaendodise G ( 5 ), mussaendodise U ( 6 ), mussaendodise P ( 7 ), and mussaglaoside B ( 8 ) have been isolated from Mussaenda pilosissima Valeton. Their chemical structures were elucidated by spectroscopic methods, 1 D-, 2 D-NMR, and mass spectra. Compounds 1-7 showed significant inhibitory activity on LPS-stimulated NO production in BV2 cells with the IC 50 values ranging from 43.5 to 65.2 µM.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease threatening the health of the elderly, but the available therapeutic and preventive drugs remain suboptimal. Loganin, an iridoid glycoside extracted from Cornus officinalis , is reported to have anti-inflammatory and memory-enhancing properties. This study is aimed to explore the influence of loganin on cognitive function in 3xTg-AD mice and the underlying mechanism associated with its neuroprotection. According to the results of behavioral tests, we found that administration of loganin could significantly alleviate anxiety behavior and improve memory deficits of 3xTg-AD mice. Furthermore, immunohistochemical analysis displayed that there were decreased Aβ deposition in the hippocampus and cortex of 3xTg-AD mice treated with loganin compared with the control mice. Importantly, the Aβ-related pathological change was mainly involved in altering APP expression and processing. And loganin was also found to reduce the levels of phosphorylated tau (i.e. pTau S396 and pTau S262 ) in 3xTg-AD mice. By performing 2D-DIGE combined with MALDI-TOF-MS/MS, we revealed 28 differentially expressed proteins in the 3xTg-AD mice treated with loganin compared with the control mice. Notably, 10 proteins largely involved in energy metabolism, synaptic proteins, inflammatory response, and ATP binding were simultaneously detected in 3xTg-AD mice compared to WT mice. The abnormal changes of energy metabolism (PAGM1 and ENO1), synaptic proteins (SYN2 and Cplx2), inflammatory response (1433Z) were verified by western blot. Overall, our study suggested that loganin could be used as a feasible candidate drug to ameliorate molecular deficits, pathologies and cognitive impairment for prevention and treatment of AD.

Cornelian cherry ( Cornus mas L.) fruits possess potential cardiovascular, lipid-lowering and hypoglycemic bioactivities. The aim of this study is to evaluate the influence of resin-purified cornelian cherry extract rich in iridoids and anthocyanins on several transcription factors, intima/media ratio in aorta and serum parameters, which determine or are valuable indicators of the adverse changes observed in the course of atherosclerosis, cardiovascular disease, and metabolic syndrome. For this purpose, male New Zealand rabbits were fed a diet enriched in 1% cholesterol for 60 days. Additionally, one group received 10 mg/kg b.w. of cornelian cherry extract and the second group 50 mg/kg b.w. of cornelian cherry extract. PPAR-α and PPAR-γ expression in the aorta, LXR-α expression in the liver; cholesterol, triglycerides, adipokines, apolipoproteins, glucose and insulin levels in serum; the intima and media diameter in the thoracic and abdominal aorta were determined. Administration of cornelian cherry extract resulted in an enhancement in the expression of all tested transcription factors, a decrease in triglycerides, leptin and resistin, and an increase in adiponectin levels. In addition, a significant reduction in the I/M ratio was observed for both the thoracic and abdominal aorta. The results we have obtained confirm the potential contribution of cornelian cherry extract to mitigation of the risk of developing and the intensity of symptoms of obesity-related cardiovascular diseases and metabolic disorders such as atherosclerosis or metabolic syndrome.

Natural products have been the main source of bioactive molecules for centuries. We tested the biological profile of two metabolites extracted from Gentiana lutea L. by means of computational techniques and in vitro assays. The two molecules (loganic acid and gentiopicroside) were tested in silico using an innovative technique, named Inverse Virtual Screening (IVS), to highlight putative partners among a panel of proteins involved in inflammation and cancer events. A positive binding with cyclooxygenase-2 (COX-2), alpha-1-antichymotrypsin, and alpha-1-acid glycoprotein emerged from the computational experiments and the outcomes from the promising interaction with COX-2 were confirmed by Western blot, highlighting the reliability of IVS in the field of the natural products.

Loganin is an iridoid glycoside with antioxidant, anti-inflammatory, glucose-lowering activities which may address the pathological mechanisms of painful diabetic neuropathy (PDN) related to inflammation, oxidative stress, and hyperglycemia. This study investigated the underlying mechanisms of action of loganin on PDN. The in vivo model of PDN was established by streptozotocin-nicotinamide (STZ-NA) induction in Sprague Dawley (SD) rats. Subsequently, loganin (5 mg/kg) was administered by daily intraperitoneal injection. High-glucose stimulated human SH-SY5Y cells co-incubated with loganin were used to mimic the in vitro model of PDN. Loganin improved PDN rats' associated pain behaviors (allodynia and hyperalgesia), insulin resistance index (HOMA-IR), and serum levels of superoxide dismutase (SOD), catalase and glutathione. Loganin also reduced pain-associated channel protein Ca V 3.2 and calcitonin gene-related peptide (CGRP) in the surficial spinal dorsal horn of PDN rats. Loganin inhibited oxidative stress and NF-κB activation and decreased the levels of mRNA and protein of proinflammatory factors IL-1β and TNF-α. Moreover, loganin attenuated insulin resistance by modulating the JNK-IRS-1 (insulin receptor substrate-1)-Akt-GSK3β signaling pathway in PDN rats. These results suggested that loganin improved PDN-mediated pain behaviors by inhibiting oxidative stress-provoked inflammation in the spinal cord, resulting in improved neuropathic pain.

The use of botanical dietary supplements for the alleviation of conditions such as hot flashes, premenstrual syndrome, and fertility is prolific worldwide. Estrogen and progesterone receptors (ER and PR) and their corresponding steroid hormones are critical for the relief of hot flashes and the treatment of patients who develop endometriosis, and these pathways can influence the development of endometrial, ovarian, and breast cancers. However, few studies have investigated or identified the natural product components in herbal supplements that act on the PR. In the current study, a new secoiridoid, demethoxy-cornuside ( 1 ), along with six known secoiridoids ( 2 - 7 ) were isolated from the twigs of dogwood ( Cornus officinalis ) by bioassay-guided isolation with a progesterone response element (PRE)/luciferase (Luc) reporter assay in Ishikawa cells. Four phytoprogestins ( 1 , 2 , 6 , 7 ) potentiated the effect of progesterone in the PRE/Luc assay. This study demonstrates that C. officinalis components might potentiate progesterone signaling in the presence of progesterone, which could modify progesterone receptor action in hormone-responsive tissues such as the uterus and mammary gland.

Lonicerae japonicae flos (LJF) is widely used for the treatment of inflammation-related diseases in traditional Chinese medicine (TCM). To clarify the anti-inflammatory mechanism of LJF, 29 compounds with high content in LJF were selected for network pharmacology. Then, a comprehensive network pharmacology strategy was implemented, which involved compound-inflammation-target construction, protein-protein interaction (PPI) network analysis, and enrichment analysis. Finally, molecular docking and in vitro experiments were performed to verify the anti-inflammatory activity and targets of the key compound. As a result, 279 inflammation-associated proteins were identified, which are mainly involved in the AGE/RAGE signaling pathway in diabetic complications, the HIF-1 signaling pathway, the PI3K-AKT signaling pathway, and EGFR tyrosine kinase inhibitor resistance. A total of 12 compounds were linked to more than 35 targets, including apigenin, kaempferol, quercetin, luteolin, and ferulic acid. The results of molecular docking showed that AKT has the most binding activity, exhibiting certain binding activity with 10 compounds, including vanillic acid, protocatechuic acid, secologanic acid, quercetin, and luteolin; the results of qRT-PCR and WB confirmed that two key compounds, secologanic acid and luteolin, could significantly decrease the secretion of TNF- α and the AKT expression of RAW264.7 murine macrophages stimulated by LPS (lipopolysaccharide). These results demonstrate that the comprehensive strategy can serve as a universal method to illustrate the anti-inflammatory mechanisms of traditional Chinese medicine by identifying the pathways or targets., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Xiaoying Guo et al.)

M2 macrophages are associated with deposition of interstitial collagen and other extracellular matrix proteins during the course wound healing and also inflammatory response to biomaterials. Developing advanced biomaterials to promote the M2 subtype may be an effective way to improve tissue reinforcement surgery outcomes. In this study, the effect of genipin, a naturally derived crosslinking agent, on M0 → M2-polarization was investigated. Genipin was introduced either indirectly by seeding cells on aligned collagen biotextiles that are crosslinked by the agent or in soluble form by direct addition to the culture medium. Cellular elongation effects on macrophage polarization induced by the collagen biotextile were also investigated as a potential inducer of macrophage polarization. M0 and M2 macrophages demonstrated significant elongation on the surface of aligned collagen threads, while cells of the M1 subtype-maintained a round phenotype. M0 → M2 polarization, as reflected by arginase and Ym-1 production, was observed on collagen threads only when the threads were crosslinked by genipin, implicating genipin as a more potent inducer of the regenerative phenotype compared to cytoskeletal elongation. The addition of genipin to the culture medium directly also drove the emergence of pro-regenerative phenotype as measured by the markers (arginase and Ym-1) and through the activation of the pSTAT6-PPAR-gamma pathway. This study indicates that genipin-crosslinked collagen biotextiles can be used as a delivery platform to promote regenerative response after biomaterial implantation. STATEMENT OF SIGNIFICANCE: The immune response is one of the key determinants of tissue repair and regeneration rate, and outcome. The M2 macrophage subtype is known to resolve the inflammatory response and support tissue repair by producing pro-regenerative factors. Therefore, a biomaterial that promotes M2 sub-type can be a viable strategy to enhance tissue regeneration. In this study, we investigated genipin-crosslinked electrochemically aligned collagen biotextiles for their capacity to induce pro-regenerative polarization of M0 macrophages. The results demonstrated that genipin, rather than matrix-induced cellular elongation, was responsible for M0 → M2 polarization in the absence of other bioinductive factors and maintaining the M2 polarized status of macrophages. Furthermore, we identified that genipin polarizes the M2 macrophage phenotype via activation of the pSTAT6-PPAR-gamma pathway., Competing Interests: Declaration of Competing Interest Drs. Akkus and Hijaz disclose employment and equity ownership in association with CollaMedix Inc. Dr. Akkus is an inventor on a patent that is associated with electrochemical compaction of collagen as threads. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. All rights reserved.)

The changes of fibroblast-like synoviocytes (FLSs) and vascular endothelial cells (VECs) biological functions are closely related to angiogenesis in rheumatoid arthritis (RA). Nevertheless, how the crosstalk between FLSs and VECs interferes with RA is far from being clarified. Herein, we studied the effect of the reciprocal interactions between FLSs and VECs on angiogenesis and mechanism of geniposide (GE). After administration of GE, improvement of synovial hyperplasia in adjuvant arthritis rats was accompanied by downregulation of SphK1 and p-Erk1/2. The dynamic interaction between FLSs and VECs triggers the release of S1P by activating p-Erk1/2 and SphK1, then activating RhoA-F-actin and Ras-Erk1/2 pathways. When exposed to the inflammatory microenvironment mediated by FLSs-VECs crosstalk, proliferation, migration, and permeability of VECs were enhanced, the angiogenic factors were imbalanced. Meanwhile, the proliferation and secretory ability of FLSs increased. Interestingly, depletion of S1P or blocking of the activation of SphK1 by GE and PF-543 prevented the changes. In conclusion, S1P released during FLSs-VECs crosstalk changed their biological functions by activating RhoA-F-actin and Ras-Erk1/2 pathways. GE acted on p-Erk1/2 and SphK1, inhibited the secretion of S1P, and blocked the interplay between FLSs and VECs. These results provide new insights into the mechanism of angiogenesis in RA., (© 2021 John Wiley & Sons Ltd.)

Morinda officinalis How was widely applied to alleviate symptom like impotence, menstrual disorders, osteoporosis, and rheumatoid arthritis. To expand resources usage, phytochemistry of the aerial parts was studied and the structures of compounds were elucidated based on NMR, HRESIMS, IR and UV. Moreover, the anti-inflammatory effect and possible mechanism were investigated by Griess kit, RT-qPCR, ELISA, western blot and molecular docking on LPS-induced inflammation in RAW 264.7 cells. Herein, we isolated and identified 16 iridoid derivatives, including seven new iridoids officinaloside A-G (1-7) and nine known iridoids. All the compounds were safe to RAW 264.7 cells. Luckily, compounds 5 and 6 showed inhibitory effect on production of NO, and decreased the expression of inflammatory cytokines at mRNA and protein levels in a dose-dependent way. The possible mechanism of their anti-inflammation may be the affinity interaction between 5 with COX-2 protein, and 6 with iNOS protein. Overall, compounds 5 and 6 exert promising effects in inhibiting inflammatory cytokines, indicating that they could be used as lead compounds for developing health products or clinical practice for inflammation, which provides a scientific basis for further sustainable development and usage of the aerial parts of Morinda officinalis How., (Copyright © 2021. Published by Elsevier B.V.)

Two phenylpropanoid-conjugated iridoids, deglucosyl gaertneroside (1) and morindoidin (2), were isolated from the leaves of Morinda morindoides (Rubiaceae) by activity-guided fractionation using an anti-malarial activity assay. The known related iridoids molucidin (3) and prismatomerin (4), two lignans, abscisic acid, two megastigmanes, and two flavonol glycosides were also identified. The structures of isolated compounds were elucidated using spectroscopic analysis. The isolated compounds were evaluated for anti-malarial activity against the chloroquine/mefloquine-sensitive strains of Plasmodium falciparum together with cytotoxicity against adult mouse brain cells. Potent anti-malarial activity of 3 and 4 (IC 50 of 0.96 and 0.80 μM, CC 50 of 1.02 and 0.88 μM, and SI of 1.06 and 1.10, respectively) was shown, while new iridoids 1 and 2 and pinoresinol (5) displayed moderate activity (IC 50 of 40.9, 20.6, and 24.2 μM) without cytotoxicity (CC 50  > 50 μM). These results indicate that 1-5 may be promising lead compounds for anti-malarial drugs. In addition, our results imply the necessity of the quality control of the extract of M. morindoides leaves based on the contents of 1-5 in terms of the safety and efficacy., (© 2021. The Japanese Society of Pharmacognosy.)

Rehmannia glutinosa, the fresh or dried root of Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & Mey., and Gardenia, the fruit of Gardenia jasminoides Ellis from Rubiaceae, both are famous traditional Chinese medicines that have been traditionally used in China. Catalpol and geniposide, as two kinds of iridoid glycosides with high activities, are the main bioactive components in Rehmannia glutinosa and Gardenia jasminoides Ellis, respectively. Over the past few decades, catalpol and geniposide have been widely studied for their therapeutic effects. The preclinical experiments demonstrated that they possessed significant neuroprotective activities against Alzheimer's disease, Parkinson's disease, stroke, and depression, etc. In this paper, the pharmacological effects and mechanisms of catalpol and geniposide on Alzheimer's disease and Parkinson's disease from 2005 to now were systematically summarized and comprehensively analyzed. At the same time, the pharmacokinetic characteristics of the analyzed compounds were also described, hoping to provide some enlightenment for the design, research, and development of iridoid glycosides., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: Genipin-1-β-d-gentiobioside (GG) is a kind of compound extracted from Gardenia jasminoides Ellis. The chemical structure of GG is similar to that of geniposide and has antidiabetic effects. We aimed to investigate the efficacy of GG on diabetic nephropathy (DN) in vivo and in vitro experiments and explore its potential mechanism., Methods: For high-fat diet/streptozotocin-induced DN mice used in our study, the general features of mice were analysed after GG treatment. Oxidative stress parameters and inflammatory factors were also measured by commercial kits. Kidney damage was assessed using hematoxylin and eosin (H&E), periodic acid-Schiff (PAS) and Masson staining, respectively. In vitro, podocyte injury was assessed by TUNEL and flow cytometric analyses. AMP-activated protein kinase/silencing information regulator related enzyme 1 (AMPK/SIRT1)/nuclear factor-κB (NF-κB) pathway-related proteins were detected by AMPK-siRNA intervention and western blotting., Key Findings: Treatment of GG could increase cell survival and attenuated kidney damage. Despite the presence of inflammatory and oxidative stress, when GG retained the expression of AMPK/SIRT1, it could be observed that the downstream NLRP3 inflammatory-related proteins were inhibited., Conclusions: Results showed that the protective efficacy of GG on DN works together with hypoglycemia and suppressing oxidative stress and inflammation, which at least partly involved in APMK/SIRT1/NF-κB-dependent pathway., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Plants are the everlasting source of a wide spectrum of specialized metabolites, characterized by wide variability in term of chemical structures and different biological properties such antiviral activity. In the search for novel antiviral agents against Human Immunodeficiency Virus type 1 (HIV-1) from plants, the phytochemical investigation of Scrophularia trifoliata L. led us to isolate and characterize four flavonols glycosides along with nine iridoid glycosides, two of them, 5 and 13 , described for the first time. In the present study, we investigated, for the first time, the contents of a methanol extract of S. trifoliata leaves, in order to explore the potential antiviral activity against HIV-1. The antiviral activity was evaluated in biochemical assays for the inhibition of HIV-1Reverse Transcriptase (RT)-associated Ribonuclease H (RNase H) activity and HIV-1 Integrase (IN). Three isolated flavonoids, rutin, kaempferol-7- O -rhamnosyl-3- O -glucopyranoside, and kaempferol-3- O -glucopyranoside, 8 - 10 , inhibited specifically the HIV-1 IN activity at submicromolar concentration, with the latter being the most potent, showing an IC 50 value of 24 nM.

Recent studies show that the expression of CCND1, a key factor in cell cycle control, is increased following the progress and deteriotation of glioma and predicts poor outcomes. On the other hand, dysregulated deubiquitinase USP10 also predicts poor prognosis for patients with glioblastoma (GBM). In the present study, we investigated the interplay between CCND1 protein and USP10 in GBM cells. We showed that the expression of CCND1 was significantly higher in both GBM tissues and GBM-derived stem cells. USP10 interacted with CCND1 and prevented its K48- but not K63-linked polyubiquitination in GBM U251 and HS683 cells, which led to increased CCND1 stability. Consistent with the action of USP10 on CCND1, knockdown of USP10 by single-guided RNA downregulated CCND1 and caused GBM cell cycle arrest at the G1 phase and induced GBM cell apoptosis. To implement this finding in the treatment of GBMs, we screened a natural product library and found that acevaltrate (AVT), an active component derived from the herbal plant Valeriana jatamansi Jones was strikingly potent to induce GBM cell apoptosis, which was confirmed by the Annexin V staining and activation of the apoptotic signals. Furthermore, we revealed that AVT concentration-dependently suppressed USP10-mediated deubiquitination on CCND1 therefore inducing CCND1 protein degradation. Collectively, the present study demonstrates that the USP10/CCND1 axis could be a promising therapeutic target for patients with GBMs., (© 2020. CPS and SIMM.)

The serotonin (5-hydroxytryptamine) type 3 receptor is an important target in the control of digestive dysfunction such as anorexia and bulimia, and 5-HT 3 receptor antagonists are effective against eating disorder and the early-phase chemotherapy and radiotherapy evoked vomiting. Our previous research of Valeriana jatamansi revealed the presence of iridoids, which showed potent antitumor activities. Here, we explored the effects of 10π aromatic iridoid desacylbaldrinal isolated from V. jatamansi on the 5-HT 3 receptor current. We performed whole cell recordings of 5-HT 3 A receptor currents in the presence of the compound. The result indicated that desacylbaldrinal inhibited the 5-HT-mediated 5-HT 3 A receptor current.

Alzheimer's disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules is considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The VEGF/SphK1/S1P pathway is closely related to angiogenesis in rheumatoid arthritis (RA), but the precise underlying mechanisms are unclear at present. Here, we explored the involvement of the VEGF/SphK1/S1P cascade in RA models and determined the effects of GE intervention. Our results showed abnormal expression of proteins related to this pathway in RA synovial tissue. Treatment with GE effectively regulated the signal axis, inhibited angiogenesis, and alleviated RA symptoms. In vitro, TNF-ɑ enhanced the VEGF/SphK1/S1P pathway in a co-culture model of fibroblast-like synoviocytes (FLS) and vascular endothelial cells (VEC). GE induced downregulation of VEGF in FLS, restored the dynamic balance of pro-/antiangiogenic factors, and suppressed SphK1/S1P signaling in VEC, resulting in lower proliferation activity, migration ability, tube formation ability, and S1P secretion ability of VEC cells. Additionally, SphK1-specific small interfering RNA (siRNA) blocked the VEGF/SphK1/S1P cascade, which can effectively alleviate the stimulatory effect of FLS on VEC and further enhanced the therapeutic effect of GE. Taken together, our results demonstrate that GE suppresses the VEGF/SphK1/S1P pathway and alleviates the stimulation of VEC by FLS, thereby preventing angiogenesis and promoting therapeutic effects against RA., (© 2021 John Wiley & Sons Ltd.)

Endoplasmic reticulum (ER) stress and uncoupling protein-2 (UCP2) activation are opposing modulators of endothelial dysfunction in atherosclerosis. Exercise reduces atherosclerosis plaques and enhances endothelial function. Our aim was to understand how exercise affects ER stress and UCP2 activation, and how that relates to endothelial dysfunction in an atherosclerotic murine model. Wild type (C57BL/6, WT) and apolipoprotein-E-knockout (ApoE tm1Unc , ApoE KO) mice underwent treadmill exercise training (EX) or remained sedentary for 12 weeks. Acetylcholine (ACh)-induced endothelium-dependent vasodilation was determined in the presence of an eNOS inhibitor (L-NAME), UCP2 inhibitor (genipin), and ER stress inducer (tunicamycin). UCP2, ER stress markers and NLRP3 inflammasome signaling were quantified by western blotting. p67 phox and superoxide were visualized using immunofluorescence and DHE staining. Nitric oxide (NO) was measured by nitrate/nitrite assay. ACh-induced vasodilation was attenuated in coronary arterioles of ApoE KO mice but improved in ApoE KO-EX mice. Treatment of coronary arterioles with L-NAME, tunicamycin, and genipin significantly attenuated ACh-induced vasodilation in all mice except for ApoE KO mice. Exercise reduced expression of ER stress proteins, TXNIP/NLRP3 inflammasome signaling cascades, and Bax expression in the heart of ApoE KO-EX mice. Further, exercise diminished superoxide production and NADPH oxidase p67 phox expression in coronary arterioles while simultaneously increasing UCP2 expression and nitric oxide (NO) production in the heart of ApoE KO-EX mice. Routine exercise alleviates endothelial dysfunction in atherosclerotic coronary arterioles in an eNOS, UCP2, and ER stress signaling specific manner, and resulting in reduced TXNIP/NLRP3 inflammasome activity and oxidative stress., (© 2021. The Author(s).)

Eleven new iridoids, brachybones A-K ( 1 - 11 ), were isolated from the twigs of Viburnum brachybotryum . Their structures including absolute configurations were determined by spectroscopic data analysis and from the electronic circular dichroism (ECD) spectra. All of the compounds 1 - 11 possess one or two acetoxysenecioate substituents. Furthermore, compounds 5 - 7 and 11 feature a Cl atom in the molecule, while compounds 9 - 11 exhibit a cagelike rigid skeleton through an unusual oxo bridge from C-3 to C-8 or C-10. The isolates were evaluated for cytotoxic activity against the HCT-116, A549, and Hela cell lines, and the results showed compounds 10 and 11 to be active against HCT-116 cells.

Age-related macular degeneration (AMD), mainly wet AMD, is the major reason for nonreversible vision loss worldwide. Choroidal neovascularization (CNV) is a characteristic pathological manifestation of wet AMD. Stress or injury to the retinal pigment epithelium (RPE) induces proangiogenic factors that drive CNV. An iridoid glycoside extracted from the fruit of gardenia, geniposide (GEN) plays an antiangiogenic role. In this study, GEN inhibited the transcription and expression of heparin-binding epidermal growth factor (HB-EGF), a proangiogenic factor, in hypoxic RPE cells and a mouse laser-induced CNV model. Inhibition of glucagon-like peptide-1 receptor (GLP-1R), a GEN receptor blocker, eliminated the protective effect of GEN. Additionally, GEN decreased the transcription and expression of HB-EGF in hypoxia-exposed RPE cells by downregulating the miR-145-5p/NF-κB axis. Therefore, our research provides a promising novel strategy for wet AMD therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cerebral ischemia causes severe neurological disorders and neuronal dysfunction. Baicalin (BC), geniposide (GP), and their combination (BC/GP) have been shown to inhibit post-ischemic inflammatory injury by inhibiting the 5-LOX/CysLTs pathway. The aims of this study were to observe the inhibitory effects of BC/GP on the activation of microglial cells induced by oxygen glucose deprivation and reoxygenation (OGD/R) and to investigate whether the 5-LOX/LTB4 pathway was involved in these effects. Molecular docking showed that BC and GP exhibited considerable binding activity with LTB4 synthase LTA4H. BV-2 microglia were transfected with a 5-LOX overexpression lentiviral vector, and then OGD/R was performed. The effects of different concentrations of BC, GP, and BC/GP (6.25 μM, 12.5 μM, and 25 μM) on cell viability and apoptosis of microglia were evaluated by MTT and flow cytometry. The expression of TNF-α, IL-1β, NF-κB, and pNF-κB also was measured by ELISA, Western blots and immunofluorescence. Western blots and qRT-PCR analysis were used to determine the levels of CD11b, CD206, and 5-LOX pathway proteins. Results showed that BC, GP, and BC/GP reduced the apoptosis caused by OGD/R in a dose-dependent manner, and cell viability was significantly increased at a concentration of 12.5 μM. OGD/R significantly increased the release of TNF-α, IL-1β, NF-κB, pNF-κB, and CD11b. These effects were suppressed by BC, GP, and BC/GP, and the OGD/R-induced transfer of NF-κB p65 from the ctytoplasm to the nucleus was inhibited in microglia. Interestingly, the LTB4 inhibitor, U75302, exhibited the same effect. Also, BC, GP, and BC/GP significantly reduced the expression of 5-LOX pathway proteins. These results demonstrated that BC/GP inhibited OGD/R-induced polarization in BV2 microglia by regulating the 5-LOX/LTB4 signaling pathways and attenuating the inflammatory response. Our results supported the theoretical basis for additional in-depth study of the function of BC/GP and the value of determining its unique target, which might provide a new therapeutic strategy for ischemic cerebrovascular disease.

Sclerosing cholangitis, characterized by biliary inflammation, fibrosis, and stricturing, remains one of the most challenging conditions of clinical hepatology. Geniposide (GE) has anti-inflammatory, hepatoprotective, and cholagogic effects. Whether GE provides inhibition on the development of sclerosing cholangitis is unknown. Here, we investigated the role of GE in a mouse model in which mice were fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 4 weeks to induce sclerosing cholangitis. The results demonstrated that the increased hepatic gene expressions of pro-inflammatory (IL-6, VCAM-1, MCP-1, and F4/80) and profibrogenic markers (Col1α1, Col1α2, TGF-β, and α-SMA) in DDC feeding mice were reversed after treatment with GE. GE also suppressed expressions of CK19 and Ki67 in DDC-fed mice, suggesting that GE could ameliorate DDC-induced hepatocytes and cholangiocytes proliferation. In addition, GE significantly increased bile acids (BAs) secretion in bile, which correlated with induced expressions of hepatic FXR, BAs secretion transporters (BSEP, MRP2, MDR1, and MDR2), and reduced CYP7A1 mRNA expression. Furthermore, higher expressions of ileal FXR-FGF15 signaling and reduced ASBT were also observed after GE treatment. Taken together, these data showed that GE could modulate inflammation, fibrosis, and BAs homeostasis in DDC-fed mice, which lead to efficiently delay the progression of sclerosing cholangitis., (© 2021 John Wiley & Sons Ltd.)

It is well known that cells can generate endogenous forces onto the extracellular matrix, but to what extent the mechanical properties of the matrix influences these endogenous cellular forces remains unclear. We therefore sought to quantify the influence of matrix rigidity on cell-matrix interactions by inducing cross-links using increasing concentrations of genipin (0.01-1 mM) or by blocking cross-link formation using beta-aminopropionitrile (BAPN) in engineered human tendon tissue constructs. The cell-matrix mechanics of the tendon constructs were evaluated as cell-generated tissue re-tensioning and stress-relaxation responses using a novel custom-made force monitor, which can apply and detect tensional forces in real-time in addition to mechanical failure testing. Genipin treatment had no influence on the biochemical profile (hydroxyproline, glycosaminoglycan and DNA content) of the constructs and cell viability was comparable between genipin-treated and control constructs, except at the highest genipin concentration. Endogenous re-tension after unloading was significantly decreased with increasing genipin concentrations compared to controls. Mechanical failure testing of tendon constructs showed increased (56%) peak stress at the highest genipin concentration but decreased (72%) with BAPN treatment when compared to controls. Tendon construct stiffness increased with high genipin concentrations (0.1 and 1 mM) and decreased by 70% in BAPN-treated constructs, relative to the controls. These data demonstrate that human tendon fibroblasts regulate their force exertion inversely proportional to increased cross-link capacity but did so independently of matrix stiffness. Overall, these findings support the notion of an interaction between cell force generation and cross-linking, and thus a role for this interplay in mechanical homeostasis of the tissue., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Nutrition determines our health, both directly and indirectly. Consumed foods affect the functioning of individual organs as well as entire systems, e.g., the cardiovascular system. There are many different diets, but universal guidelines for proper nutrition are provided in the WHO healthy eating pyramid. According to the latest version, plant products should form the basis of our diet. Many groups of plant compounds with a beneficial effect on human health have been described. Such groups include anthocyanins and iridoids, for which it has been proven that their consumption may lead to, inter alia, antioxidant, cholesterol and lipid-lowering, anti-obesity and anti-diabetic effects. Transcription factors directly affect a number of parameters of cell functions and cellular metabolism. In the context of lipid and cholesterol metabolism, five particularly important transcription factors can be distinguished: liver X receptor (LXR), peroxisome proliferator-activated receptor-α (PPAR-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer binding protein α (C/EBPα) and sterol regulatory element-binding protein 1c (SREBP-1c). Both anthocyanins and iridoids may alter the expression of these transcription factors. The aim of this review is to collect and systematize knowledge about the impact of anthocyanins and iridoids on transcription factors crucial for lipid and cholesterol homeostasis.

Punicalagin (PA) not only binds type II collagen, but also blocks its MMP-13-mediated degradation, and genipin (GNP) is a collagen cross-linking agent. We hypothesized that these drugs could mitigate the loss of cartilage if administered in the early phase of osteoarthritis, and experiments were designed to provide proof-of-concept. Porcine cartilage was exposed to both drugs in a manner designed to simulate intra-articular (IA) injection. Based on penetration of PA into cartilage, the rate of drug diffusion was conservatively estimated at 2 μm per minute. GNP caused a measurable degree of cross-linking, increased compressive resistance and coefficient of friction, and substantially inhibited degradation by collagenase, but not by hyaluronidase. Pre-incubation of GNP with collagenase had no effect on enzymatic activity. PA did not cross-link collagen nor affect the mechanical properties of cartilage. It did, however, increase resistance to degradation by collagenase and hyaluronidase. Furthermore, it reacted with collagenase in solution and inhibited its subsequent enzymatic activity. Effects of PA and GNP were not additive. The chondroprotective effect of semi-weekly IA injections was investigated in the monoiodoacetate-induced model of OA in rats. Quantitative histology suggested that injection of PA decreased the amount of cartilage lost compared to saline-injected controls, and the addition of GNP made no difference. This study supports the notion that IA delivery of PA could mitigate OA-induced cartilage erosion., (© 2020 Wiley Periodicals LLC.)

Sepsis is a systemic inflammatory response syndrome resulted from severe infection. Excessive inflammation response plays an important role in sepsis-induced acute lung injury (ALI). Loganin is an iridoid glycoside isolated from Corni fructus and exerts an anti-inflammatory effect in multiple inflammatory diseases; however, the role of loganin in sepsis-induced ALI remains unknown. In the current study, the cecal ligation and puncture (CLP)-induced murine sepsis model was constructed to investigate the anti-inflammatory property of loganin in sepsis-induced ALI. Lipopolysaccharide (LPS)-treated Raw 264.7 cells and primary murine peritoneal macrophages were established to further explore underlying mechanism of loganin. Results showed that intragastrical administration of loganin significantly increased murine survival, reduced the alveolar structure damage and inflammatory cell infiltration. Loganin suppressed the release of the M1 macrophage-associated pro-inflammatory cytokines and induced the activation of M2-type anti-inflammatory cytokines. Besides, loganin dramatically inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent IL-1β secretion. Further in vitro studies confirmed that loganin efficiently inhibited M1 macrophage polarization and NLRP3 inflammasome activation by blocking the extra-cellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways. Taken together, the anti-inflammatory effect of loganin in sepsis-induced ALI was associated with the ERK and NF-κB pathway-mediated macrophage polarization and NLRP3 inflammasome activation. Our study offers a favorable mechanistic basis to support the therapeutic potential of loganin in anti-inflammatory diseases, such as sepsis-induced ALI., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide. Activation of Kupffer cells (KCs) is central to the development of diet-induced NASH. We investigated whether a combination of two active chemical components, geniposide and chlorogenic acid (GC), at a specific ratio (67 : 1), ameliorates diet-induced NASH and the underlying mechanisms involved. C57BL/6J mice exposed to a high-fat and high-cholesterol (HFHC) diet containing cholesterol, choline, and high-sugar drinking water, as well as RAW264.7 cells stimulated with lipopolysaccharide (LPS) were studied. The combination exerted a therapeutic effect on HFHC-induced NASH in mice. Simultaneously, GC was found to reduce the expression of cytokines secreted by hepatic macrophages, including tumor necrosis factor- α (TNF- α ), interleukin-1 α (IL-1 α ), IL-1 β , IL-6, monocyte chemotactic protein 1 (MCP-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Moreover, GC reduced the number of KCs expressing F4/80. Furthermore, TNF- α , inducible nitric oxide synthase (INOS), IL-1 β , and IL-6 mRNA and TNF- α protein expression levels were suppressed upon GC treatment in RAW264.7 cells. Our findings suggest that GC has a strong anti-inflammatory effect in NASH, and this effect can be attributed to the suppression of KC activity in the liver., Competing Interests: The authors declare no potential conflicts of interest., (Copyright © 2021 Xin Xin et al.)

Background: Valtrate is a novel epoxy iridoid ester isolated from Chinese herbal medicine Valeriana jatamansi Jones with anti-proliferative activity against various human cancer cell lines. However, its efficacy and molecular mechanisms against pancreatic cancer (PC) cells are largely unclear., Purpose: To investigate the anti-cancer effects of valtrate on PC cell lines and its underlying mechanisms., Methods: MTT assay was first performed to detect the effect of valtrate on cell viability in human PC cell lines and normal pancreatic epithelial cells HPDE. Cell apoptosis and cycle phase assay were detected by flow cytometry. The relative mRNA expressions of Bax, Bcl-2, c-Myc, and CyclinB1 were tested by quantitative PCR (qPCR) assay. The expression of relative proteins was detected by Western blotting (WB). A PANC-1 luc cells xenograft mouse model in nu/nu female mice was used to elucidate the effect of valtrate on tumor growth in vivo., Results: Valtrate significantly inhibited the growth of PC cells without affecting the growth of normal pancreatic epithelial cells HPDE, induced significant apoptosis and cell cycle arrest in G2/M phase. Moreover, valtrate inhibited the tumor growth of PC cell PANC-1 in xenograft mice by 61%. Further mechanism study demonstrated that valtrate could increase the expression level of Bax, suppress Bcl-2 as well as c-Myc and Cyclin B1, inhibit the transcriptional activity of Stat3, while valtrate decreased the expression level of Stat3 and phosphated-Stat3 (Tyr705) and induced the high molecular aggregation of Stat3. Molecular docking analysis predicted that valtrate might interact with Cys712 of Stat3 protein. Valtrate could also induce a transient depleted intracellular glutathione (GSH) level and increased reactive oxygen species (ROS). NAC (N-acetylcysteine), a reducer reversed valtrate-induced the depletion of Stat3, p-Stat3, c-Myc, and Cyclin B1., Conclusion: Valtrate exerts anti-cancer activity against PC cells by directly targeting Stat3 through a covalent linkage to inhibit Stat3 activity, which causes apoptosis and cell cycle arrest., (Copyright © 2021. Published by Elsevier GmbH.)

The purpose of this study was to investigate the antidepressant mechanism of GEN (geniposide) on depression mice induced by LPS. The mice were intragastrically treated with GEN (10 mg/kg/d or 40 mg/kg/d) or ibrutinib for continuous 7 days prior to LPS injection. The anxiety- and depression-like behaviors of mice were assessed via behavioral tests (sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open-field test (OFT)). Microglial BV2 cells were treated with GEN or/and ibrutinib and stimulated with LPS. The productions of pro-inflammatory cytokines IL-6 and TNF-α in hippocampus, serum, and supernatant were detected by ELISA. The correlative proteins BTK, p-BTK, JAK2, p-JAK2, STAT1, p-STAT1, BDNF, TrkB, and p-TrkB were assessed through western blot. As a result, GEN ameliorated the anxiety- and depression-like behaviors of mice in behavioral tests. GEN treatment also regulated microglia polarization towards anti-inflammatory phenotype M2 and inhibited the production of pro-inflammatory cytokines IL-6 and TNF-α. In addition, with the application of ibrutinib, the selective inhibitor of BTK, it was proclaimed that the administration of GEN restrained the activation of JAK2/STAT1 pathway via attenuating the hyperphosphorylation of BTK both in mice and BV2 cells. Furthermore, it was also found that GEN activated BDNF/TrkB neuroprotective signaling pathway through the reduction of BTK phosphorylation. From the overall results, we suggested that GEN exerted a beneficial effect on LPS-induced depression in mice possibly through the modulation of BTK/JAK2/STAT1 signaling., (Copyright © 2021 Elsevier Inc. All rights reserved.)