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Millingtonia hortensis L.f., commonly known as tree jasmine or Indian cork tree, is native to South Asia and Southeast Asia. Traditionally, its stem bark, leaves, and roots are employed for pulmonary, gastrointestinal, and antimicrobial purposes, while the flowers are used in treating asthma and sinusitis. Aim of the study: The underlying anti-inflammatory mechanisms of M. hortensis remain relatively unexplored. Therefore, we studied the anti-inflammatory effects of M. hortensis and the molecular mechanisms of its ethanol extracts (Mh-EE) both in vitro and in vivo. Nitric oxide (NO) production was assessed using Griess reagent, while cell viability of RAW264.7 cell and HEK293T cells were determined via the MTT assay. Constituent analysis of Mh-EE using GC/MS-MS and HPLC, and mRNA expression of inflammatory cytokines was measured through PCR and RT-PCR. Protein levels were analyzed using western blotting. The thermal stability of Mh-EE was evaluated by CESTA. Lastly, a gastritis in vivo model was induced by HCl/EtOH, and protein expression levels were measured using western blotting. Mh-EE significantly reduced NO production in LPS-induced RAW264.7 cells without substantially affecting cell viability. Additionally, Mh-EE decreased the expression of proinflammatory factors, such as iNOS, IL-1β and COX2. Furthermore, Mh-EE downregulated TLR4 expression, altered MyD88 recruitment, and suppressed phosphorylation of Syk, IKKα, IκBα and AKT. Simultaneously, Mh-EE also attenuated NF-κB signaling in HCl/EtOH-induced mice. Mh-EE exerts anti-inflammatory effects by suppressing p-Syk in the NF-κB pathway, and it has potential as a novel treatment agent for inflammatory diseases. [Display omitted] • Mh-EE exhibits anti-inflammatory activities both in vitro and in vivo. • Mh-EE targets Syk kinase in its anti-inflammatory mechanism. • Mh-EE holds the potential to serve as a novel therapeutic agent for inflammatory diseases. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Ecliptae herba, also known as “Mo-Han-Lian”, has long been used in China to nourish Kidney and thereafter strengthen bones. Accumulating evidence indicates that extracts of Ecliptae herba have antiosteoporotic effect. However, the effective compounds and cellular mode of action are still unclear. To investigate the effect of ethyl acetate extract of Ecliptae herba (EAE) and its component wedelolactone on proliferation and differentiation of preosteoclastic RAW264.7 cells as well as proliferation of bone marrow stromal cells (BMSC). Materials and methods RAW264.7 and BMSC were examined for proliferation by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method. Tartrate-resistant acid phosphatase (TRAP) activity of RAW264.7 was measured by using p -nitrophenyl sodium phosphate (pNPP) assay after the cells were treated with 30 ng/ml receptor activator for nuclear factor-κ B ligand (RANKL) plus various concentrations of EAE, wedelolactone or alendronate. The formation of multinucleated TRAP-positive RAW264.7 cells was observed by using a TRAP-staining kit. Results Treatment of RAW264.7 cells with EAE at high doses (20 µg/ml and 40 µg/ml) or wedelolactone at 10 µg/ml resulted in a decrease in proliferation of RAW264.7 cells. Low doses of EAE (5, 10 µg/ml) and wedelolactone (2.5 µg/ml) inhibited RANKL-induced TRAP activity by 20.3%, 37.9%, and 48.3%. The inhibitory effect of wedelolactone is more potent than that of alendronate, an anti-resorptive drug. Morphological changes revealed that 5 µg/ml EAE and 2.5 µg/ml wedelolactone reduced the number of multinucleated osteoclast-like cells. At the high doses, EAE (20 µg/ml) and wedelolactone (10 µg/ml) inhibited the growth of BMSC. Conclusions EAE and its component wedelolactone inhibited osteoclast RAW264.7 proliferation and differentiation at the low doses, but at the high doses, showed cytotoxic effect on BMSC. These results indicated that EAE and wedelolatone might be potential alternative therapy for osteoporosis. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Monochasma savatieri Franch. ex Maxim is used for treating many diseases in Traditional Chinese Medicine. Aim of the study: The present study was designed to evaluate antibacterial, anti-inflammatory activities and toxicity of the total phenylethanoid glycosides from Monochasma savatieri Franch. ex Maxim (TPG). Materials and methods: The antibacterial activity of TPG was checked by MIC and MBC in vitro; survival of mice with Pseudomonas aeruginosa or Staphylococcus aureus infection-induced sepsis was investigated to evaluate antibacterial activity of TPG in vivo. Additionally, antibacterial activities of TPG were also investigated in a Pseudomonas aeruginosa infection-induced pneumonia in the mice model. Cotton pellet induced granuloma and xylene induced ear swelling in mice models were used to quantify the anti-inflammatory activity. Results: TPG showed a significant possess bacteriostatic properties against five bacteria strains at a concentration between 0.0625 and 16mg/ml. Moreover, TPG has bactericidal activity against Pseudomonas aeruginosa, Streptococcus pneumoniae or Escherichia coli. TPG (60, 120, and 180mg/kg) prolonged survival rate of mice with Pseudomonas aeruginosa or Staphylococcus aureus infection-induced sepsis. In addition, TPG (180mg/kg) could reduce the bacterial colony-forming units in lung tissue. Furthermore, TPG (60–180mg/kg) had significantly reduced xylene-induced ear edema and granulomat formation induced by cotton pellet at a dose-dependent manner. In addition, administration of TPG (1.5g/kg) for 15 days did not result in toxicities in liver, kidney, spleen and thymus tissue in rats. Conclusion: These results indicated that TPG might be useful for the development of a novel treatment for respiratory infections or pneumonia caused by Pseudomonas aeruginosa or Staphylococcus aureus. [Copyright &y& Elsevier]

Aristolochic acids (AAs) are naturally occurring nitro phenanthrene carboxylic acids primarily found in plants of the Aristolochiaceae family. Aristolochic acid D (AAD) is a major constituent in the roots and rhizomes of the Chinese herb Xixin (the roots and rhizomes of Asarum heterotropoides F. Schmidt), which is a key material for preparing a suite of marketed Chinese medicines. Structurally, AAD is nearly identical to the nephrotoxic aristolochic acid I (AAI), with an additional phenolic group at the C-6 site. Although the nephrotoxicity and metabolic pathways of AAI have been well-investigated, the metabolic pathway(s) of AAD in humans and the influence of AAD metabolism on its nephrotoxicity has not been investigated yet. To identify the major metabolites of AAD in human tissues and to characterize AAD O -glucuronidation kinetics in different enzyme sources, as well as to explore the influence of AAD O -glucuronidation on its nephrotoxicity. The O -glucuronide of AAD was biosynthesized and its chemical structure was fully characterized by both 1H-NMR and 13C-NMR. Reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses were conducted to assess the crucial enzymes involved in AAD O -glucuronidation in humans. Docking simulations were performed to mimic the catalytic conformations of AAD in human UDP-glucuronosyltransferases (UGTs), while the predicted binding energies and distances between the deprotonated C-6 phenolic group of AAD and the glucuronyl moiety of UDPGA in each tested human UGT isoenzyme were measured. The mitochondrial membrane potentials (MMP) and reactive oxygen species (ROS) levels in HK-2 cells treated with either AAI, or AAD, or AAD O -glucuronide were tested, to elucidate the impact of O -glucuronidation on the nephrotoxicity of AAD. AAD could be rapidly metabolized in human liver and intestinal microsomes (HLM and HIM, respectively) to form a mono-glucuronide, which was purified and fully characterized as AAD-6- O -β-D-glucuronide (AADG) by NMR. UGT1A1 was the predominant enzyme responsible for AAD-6- O -glucuronidation, while UGT1A9 contributed to a lesser extent. AAD-6- O -glucuronidation in HLM, HIM, UGT1A1 and UGT1A9 followed Michaelis-Menten kinetics, with the K m values of 4.27 μM, 9.05 μM, 3.87 μM, and 7.00 μM, respectively. Docking simulations suggested that AAD was accessible to the catalytic cavity of UGT1A1 or UGT1A9 and formed catalytic conformations. Further investigations showed that both AAI and AAD could trigger the elevated intracellular ROS levels and induce mitochondrial dysfunction and in HK-2 cells, but AADG was hardly to trigger ROS accumulation and mitochondrial dysfunction. Collectively, UGT1A-catalyzed AAD 6- O -glucuronidation represents a crucial detoxification pathway of this naturally occurring AAI analogs in humans, which is very different from that of AAI. Aristolochic acid D (AAD), an abundant naturally occurring aristolochic acid derivative isolated from the Chinese herb Xixin (the roots and rhizomes of Asarum heterotropoides F. Schmidt), can be rapidly converted into AAD-6- O -β-D-glucuronide (AADG) in human tissue preparations. UGT1A-catalyzed AAD 6- O -glucuronidation offers a crucial detoxification pathway of this aristolochic acid derivative in humans, which is very different from that of the nephrotoxin aristolochic acid I (AAI). [Display omitted] • AAD- O -glucuronidation was a major metabolic pathway of AAD in humans. • The glucuronide was biosynthesized and characterized as AAD-6- O -β-D-glucuronide. • UGT1A1 was the predominant enzyme responsible for AAD-6- O -glucuronidation. • AAD-6- O -glucuronidation offers a crucial detoxification pathway of AAD in humans. [ABSTRACT FROM AUTHOR]

The root of Croton crassifolius has been used as a traditional Chinese medicine (TCM), called Radix Croton Crassifolius, and commonly known as "Ji Gu Xiang" in Chinese. Its medicinal value has been recorded in several medical books or handbooks, such as "Sheng Cao Yao Xing Bei Yao", "Ben Cao Qiu Yuan" and "Zhong Hua Ben Cao". It has been traditional employed for treating sore throat, stomach-ache, rheumatism and cancer. At present, there are limited studies on the evaluation of low-polarity extracts of roots in C. crassifolius. Consequently, the aim of this study was to evaluate the antitumor effect of the low-polarity extract of C. crassifolius root. Extracts were obtained by supercritical fluid extraction. The extracts were tested for antitumor effects in vitro on several cancer cell lines. A CCK-8 kit was used for further analysis of cell viability. A flow cytometer and propidium iodide staining were used to evaluate the cell cycle and apoptosis. Hoechst staining, JC-1 staining and the fluorescence probe DCFH-DA were used to evaluate apoptotic cells. Molecular mechanisms of action were analyzed by quantitative RT‒PCR and Western blotting. Immunohistochemistry was used for the evaluation of xenograft tumors in male BALB/c mice. Finally, molecular docking was employed to predict the bond between the desired bioactive compound and molecular targets. Eleven diterpenoids were isolated from low-polarity C. crassifolius root extracts. Among the compounds, chettaphanin II showed the strongest activity (IC 50 = 8.58 μM) against A549 cells. Evaluation of cell viability and the cell cycle showed that Chettaphanin II reduced A549 cell proliferation and induced G2/M-phase arrest. Chttaphanin II significantly induced apoptosis in A549 cells, which was related to the level of apoptosis-related proteins. The growth of tumor tissue was significantly inhibited by chettaphanin II in experiments performed on naked mice. The antitumor mechanism of chettaphanin II is that it can obstruct the mTOR/PI3K/Akt signaling pathway in A549 cells. Molecular docking established that chettaphanin II could bind to the active sites of Bcl-2 and Bax. Taken together, the natural diterpenoid chettaphanin II was identified as the major antitumor active component, and its potential for developing anticancer therapies was demonstrated for the first time by antiproliferation evaluation in vitro and in vivo. [Display omitted] • Eleven diterpenoids were obtained from the SFE extract of C. crassifolius roots. • Chettaphanin II showed the strongest antitumor activity against A549 cells. • Chettaphanin II inhibited A549 cell proliferation and arrested cells in G2/M-phase. • Chettaphanin II induced A549 cell apoptosis by inhibiting PI3K/AKT/mTOR pathway. • Chettaphanin II significantly inhibited the growth of tumor tissue in nude mice. [ABSTRACT FROM AUTHOR]

The skin is affected by endogenous and exogenous factors, which are the intuitive consequence expression of aging. Aging not only affects the aesthetics of the skin but also causes the decline of skin functions, leading to many skin diseases and even skin cancer. Anti-aging formula (AAF) has various biological effects such as antioxidants, regulation of intestinal flora metabolism, anti-aging, and memory improvement. However, it is not clarified whether it could be anti-aging of the skin and the anti-aging mechanism. This study aimed to investigate whether AAF could prevent skin from oxidative stress-induced senescence and explore the underlying molecular mechanisms. A mouse skin oxidative stress aging model was established based on ultraviolet (UV) irradiation, and parameters such as skin water content, melanogenesis, wrinkle production, pathological changes, and aging marker proteins were measured to elucidate whether AAF has an anti-aging effect on the skin. Subsequently, transcriptome sequencing (RNA-Seq) was used to identify target genes. An in vitro cellular senescence model was established to assess the role of AAF against cellular oxidative stress senescence by detecting senescence-related markers, while the specific mechanism of action of AAF in delaying skin senescence was elucidated by silencing or overexpression of targets. In vivo experiments demonstrated that AAF significantly increased skin water content, reduced skin sensitivity and melanin content, slowed wrinkles, improved UV-induced epidermal thickening, increased collagen fiber content, improved elastic fiber morphology, and reduced the expression of senescence proteins P21 and P16 in skin tissues. The RNA-Seq results identified chemokine receptor 2 (CXCR2) as one of the potential targets for delaying skin senescence. In vitro experiments showed that AAF markedly improved the aging phenotype, and knockdown or overexpression experiments verified the essential role of CXCR2 in the skin senescence process. Mechanistic studies suggested that AAF inhibited the P38/P53 pathway by reducing CXCR2 expression, which improved the aging phenotype, reduced oxidative damage, and ultimately delayed cellular senescence. The results reveal that AAF protects skin from oxidative stress-induced senescence by regulating the expression of critical target CXCR2, reducing P38 protein phosphorylation, and inhibiting P53 pathway activation. These discoveries implicate the potential of AAF in the protection of skin aging disease. [Display omitted] • The therapeutic effect of AAF on skin aging was investigated. • AAF was effective in improving skin aging. • CXCR2/P38/P53 pathway may be mechanism of anti-aging in AAF. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) is a major pathogen colonized in the human stomach and is implicated in gastritis, peptic ulcer, and gastric carcinoma. Antibiotics are useful for eradicating H. pylori but failed for drug resistance, making it urgent to develop effective and safe drugs. Rhizoma Coptidis was reported as one of the most effective Chinese medicines to treat H. pylori -related gastrointestinal diseases, while the precise antimicrobial mechanism remains unclear. Thus, it is of great significance to study the antimicrobial ingredients and corresponding mechanisms of Rhizoma Coptidis. To search for the most effective alkaloid against H. pylori in Rhizoma Coptidis and illustrate the probable mechanisms. Five main alkaloids in Rhizoma Coptidis were isolated. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were tested to determine the most effective one. Bacterial growth experiments, Annexin V-FITC/PI staining, TUNEL staining, and transmission electron microscopy (TEM) were performed to further study the anti- H. pylori activity of coptisine (Cop). The in vivo effect of Cop on H. pylori eradication rate and H. pylori -induced inflammation was investigated in mice. Transcriptomics was used to understand the underlying mechanism of eradicating H. pylori and reducing host inflammation. Western blot, RT-PCR, and ELISA experiments were utilized and confirmed that cagA was one of the targets of Cop. According to the MIC and MBC, Cop was the most effective alkaloid against H. pylori , especially with no drug resistance developed. In vitro experiments showed that Cop inhibited H. pylori by inducing DNA fragmentation, phosphatidylserine exposure, and membrane damage. Cop (150 mg/kg/day) effectively eradicated H. pylori in mice and reduced the levels of IL-2 and IL-6 to relieve gastric inflammation. Transcriptomic analysis revealed that virulence factor cagA was one of the hub genes associated with the inflammation-improving effect of Cop. That is, Cop could decrease the expression of CagA and subsequently reduce the translocation of CagA to gastric epithelial cells, thereby improving the morphology of hummingbird-like phenotype induced by CagA and alleviating inflammation. Cop is the most effective alkaloid in Rhizoma Coptidis and might act through multiple mechanisms for H. pylori eradication along with reducing the expression of CagA to alleviate inflammation. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The deposition of β-amyloid (Aβ) in neurons and vascular cells of the brain has been characterized in Alzheimer's disease. Ginsenoside Rg1 (Rg1) is an active components in Panax ginseng, a famous traditional Chinese medicines recorded in Compendium of Materia Medica. Present study attempted to evaluate the potential mechanisms of Aβ-mediated insult and the protective effects of Rg1 on human endothelial cells. Rg1 attenuated the Aβ25–35-associated mitochondrial apoptotic events, accompanied by inhibiting HIF-1α expression followed by intracellular reactive nitrogen species generation, and protein nitrotyrosination. These protective effects were abolished by glucocorticoid receptor (GR) antagonist RU486 or p-ERK inhibitor U0126 rather than estrogen receptor α antagonist ICI 82,780. Taken together, our results suggested that Rg1 protected against Aβ25–35-induced apoptosis at least in part by two complementary GR-dependent ERK phosphorylation pathways: (1) down-regulating HIF-1α initiated protein nitrotyrosination, and (2) inhibiting mitochondrial apoptotic cascades. These data provided a novel insight to the mechanisms of Rg1protective effects on Aβ25–35-induced endothelial cells apoptosis, suggesting that GR-ERK signaling pathway might play an important role in it. [Copyright &y& Elsevier]

Compound Agrimony Enteritis Capsules (FFXHC) is an ethnomedicine derived from Yi Nationality Herbal Medicine for the treatment of enteritis. We found that compared to berberine hydrochloride (BBR), a component of this medicine, FFXHC was more efficacious in the mouse model of IC mice in significantly alleviating lung and intestinal lesions. " Our study provides a novel perspective into the pharmacological mechanism of action of the ethnic compound FFXHC. To determine the underlying mechanism of the superiority of FFXHC over BBR in IC. The susceptibility of Candida albicans to FFXHC was evaluated in vitro. The mouse model of IC was established and the survival rate, weight change, the number of organ colonies, and immune organ coefficient of the mice were determined, the effect of FFXHC on the immune function of mice, including changes in the number of immune cells, levels of the related inflammatory cytokines (INF-γ, TNF-α, MCP-1, IL-6, and IL-17A), and the antimicrobial peptide, LL-37 (CRAMP in mice), were determined. Mice feces were collected and changes in the intestinal microecology were studied. Our findings indicated that FFXHC was not active against Candida albicans and did not restore the sensitivity of the resistant strain in vitro ; however, it had a therapeutic effect that improve survival rate on mice with IC. The number of lymphocytes and neutrophils of mice with IC treated with FFXHC increased significantly. The intestinal microecology of mice was restored and the abundance of the probiotic Bacteroides was increased, which further stimulated the production of the antimicrobial peptide, LL-37, which is required for acquired immunity. Furthermore, the levels of Th cell-related cytokines, including INF-γ, TNF-α, and IL-17A were significantly increased, whereas those of the proinflammatory cytokines, IL-6 and MCP-1, decreased. With the activation of acquired immunity, the immune function of mice was restored, the body weight and survival rate of mice improved considerably, the coefficients of the thymus and spleen increased, and the number of fungal colonies in the lung and kidney decreased. FFXHC could eliminate fungi by increasing the relative abundance of probiotics in Bacteroides and the number of neutrophils, thereby promoting the production of CRAMP and resulting in a fungicidal effect, leading to acquired immunity. Although BBR has an antifungal effect, we found that it was not as effective as FFXHC. [Display omitted] [ABSTRACT FROM AUTHOR]

Terminalia chebula Retz. (T.chebula) is an important medicinal plant in Tibetan medicine and Ayurveda. T.chebula is known as the "King of Tibetan Medicine", due to its widespread clinical pharmacological activity such as anti-inflammatory, antioxidative, antidiabetic as well as anticancer in lots of in vivo and in vitro models. In this study, we use transgenic and/or RNAi Caenorhabditis elegans (C.elegans) model to simulation the AD pathological features induced by Aβ, to detect the effect of TWE on improving Aβ-induced toxicity and the corresponding molecular mechanism. The study aimed to tested the activities and its possible mechanism of T.chebula to against Aβ 1-42 induced toxicity and Aβ 1-42 aggregation. Using transgenic C.elegans strain CL2006 and CL4176 as models respond to paralytic induced by Aβ toxicity. The transcription factors DAF-16 and SKN-1 were analyzed used a fluorescence microscope in transgenic strains (DAF-16:GFP, SKN-1:GFP). The function of DAF-16 and SKN-1 was further investigated using loss-of-function strains by feeding RNA interference (RNAi) bacteria. To evaluate the aggregation level of Aβ in the transgenic C.elegans , Thioflavin S (ThS) staining and WB visualized the levels of Aβ monomers and oligomers. TWE treatment can significantly improve the paralysis of transgenic C.elegans caused by Aβ aggregation (up to 14%). The Aβ aggregates in transgenic C.elegans are significantly inhibited under TWE exposure (up to 70%). TWE increases the nuclear localization of the key transcription factor DAF-16 and HSF-1, which in turn leads to the expression of downstream Hsp-16.2 protein and exerts its inhibitory effect on Aβ aggregation. Meanwhile, paralysis improved has not observed in SKN-1 mutation and/or RNAi C.elegans. Our results indicate that TWE can protect C.elegans against the Aβ 1-42 -induced toxicity, inhibition Aβ 1-42 aggregation and delaying Aβ-induced paralysis. The neuroprotective effect of TWE involves the activation of DAF-16/HSF-1/Hsp-16.2 pathway. Image 1 • The T.chebula water extract (TWE) can delay the paralysis induced by Aβ in transgenic and/or RNA interference C.elegans. • TWE shares protective function via reducing the production of Aβ oligomers. • TWE plays better effect of delaying Aβ-induced paralysis than the ethanol extract. • TWE has the physiological function of cognitive improvement. [ABSTRACT FROM AUTHOR]