Exploring the molecular mechanism of Epimedium for the treatment of ankylosing spondylitis based on network pharmacology, molecular docking, and molecular dynamics simulations.

Ankylosing spondylitis (AS) is a rheumatic disease that causes inflammation and bone formation in the spine. Despite significant advances in treatment, adverse side effects have triggered research into natural compounds. Epimedium (EP) is a traditional Chinese herb with a variety of pharmacological activities, including antirheumatic, anti-inflammatory, and immunomodulatory activities; however, its direct effects on AS treatment and the underlying molecular mechanisms have not been systematically studied. Thus, here, we used network pharmacology, molecular docking, and molecular dynamics simulations to explore the targets of EP for treating AS. We constructed an interaction network to elucidate the complex relationship between EP and AS. Sixteen active ingredients in EP were screened; 80 potential targets were identified. In particular, 8-(3-methylbut-2-enyl)-2-phenylchromone, anhydroicaritin, and luteolin were the core components and TNF, IL-6, IL-1ß, MMP9, and PTGS2 were the core targets. The GO and KEGG analyses indicated that EP may modulate multiple biological processes and pathways, including the AGE-RAGE, TNF, NF-κB/MAPK, and TLR signaling pathways, for AS treatment. Molecular docking and molecular dynamics simulations showed good affinity between the active components and core targets of EP, with stable binding within 100 nanoseconds. In particular, 8-(3-methylbut-2-enyl)-2-phenylchromone possessed the highest free energy of binding to PTGS2 and TNF (-115.575 and - 87.676 kcal/mol, respectively). Thus, EP may affect AS through multiple pathways, including the alleviation of inflammation, oxidative stress, and immune responses. In summary, we identified the active components and potential targets of EP, highlighting new strategies for the further experimental validation and exploration of lead compounds for treating AS.

Application of a meshed artificial dermal scaffold and negative-pressure wound therapy in the treatment of full-thickness skin defects: a prospective in vivo study.

Artificial dermal scaffolds (ADSs) have great value in repairing deep skin defects. However, problems such as unsatisfactory angiogenesis and local dropsy or empyema often occur, resulting in delayed or even failed wound healing. Negative pressure wound therapy (NPWT) is an effective therapy to promote wound healing or shorten wound bed preparation time. Studies on whether it can improve the effects of ADSs have never been interrupted, and no consensus has been reached. In this study, an improved ADS was prepared by mesh technology, physicochemical experiments were conducted, cell adhesion and proliferation were assessed with the meshed ADS, and in vivo experiments were conducted to investigate the effects of meshed ADS or ADS combined with NPWT in repairing full-thickness skin defects. The results showed that the meshed ADS showed through-layer channels arranged in parallel longitudinal and transverse intersections. The cell experiments confirmed the good cytocompatibility. The in vivo experiments showed that there were no differences in the take rate or contraction of grafted skin among all experiment groups. The meshed ADS exhibited good histocompatibility, and there were no differences in tissue inflammation, dermal angiogenesis, or degradation among all groups. In addition, necrosis, dropsy, or empyema of the dermal scaffold were found in all experiment groups except for the meshed ADS + NPWT group, which showed better wound repair results, including fewer scaffold-related complications and satisfactory skin graft survival and wound contraction. In conclusion, this novel meshed ADS, which has a regular through-layer mesh structure and possesses stable physicochemical properties and good biocompatibility, combined with NPWT can ensure adequate subdermal drainage and reduce the risk of scaffold-related complications, thereby improving the quality and efficiency of wound repair, promoting a broader application of biomaterials, and helping physicians and readers implement more effective wound management.

Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review.

Hyperlipidemia is a metabolic disorder, which is a major risk factor for atherosclerosis, stroke, and coronary heart disease. Although lipid-lowering treatments have been extensively studied, safer treatments with fewer adverse effects are needed. Rhubarb is a traditional Chinese medicine that has lipid-lowering, anti-inflammatory, and antioxidant properties. Disturbance in lipid metabolism is the basis of tissue damage caused by hyperlipidemia and plays a key role in the development of hyperlipidemia; however, the molecular mechanisms by which rhubarb regulates lipid metabolism to lower lipid levels are yet to be elucidated. We conducted this study to summarize the phytochemical constituents of Rheum officinale and provide a comprehensive review of the molecular mechanisms underlying the regulation of lipid metabolism during hyperlipidemia treatment. It was found that rhubarb extracts, including emodin, rhubarb acid, and rhubarb phenol, regulate total cholesterol, triglyceride, TNF-α, and IL-1ß levels through signaling pathways such as C/EBP α, 3T3-L1, PPAR α, and AMPK, thereby improving the hyperlipidemic state. This suggests that rhubarb is a natural drug with lipid-lowering potential, and an in-depth exploration of its lipid-lowering mechanism can provide new ideas for the prevention and treatment of hyperlipidemia.

The biosynthesis of EGCG, theanine and caffeine in response to temperature is mediated by hormone signal transduction factors in tea plant (Camellia sinensis L.).

As the main flavor components of tea, the contents of epigallocatechin-3-gallate (EGCG), theanine and caffeine are regulated by ambient temperature. However, whether the biosynthesis of EGCG, theanine and caffeine in response to temperature is regulated by endogenous hormones and its mechanism is still unclear. In this study, tea cuttings cultivated in the phytotron which treated at different temperatures 15℃, 20℃, 25℃ and 30℃, respectively. The UPLC and ESI-HPLC-MS/MS were used to determine the contents of EGCG, theanine, caffeine and the contents of phytohormones in one leaf and a bud. The results showed that indoleacetic acid (IAA), gibberellin 1(GA1) and gibberellin 3 (GA3) were significantly correlated with the content of EGCG; Jasmonic acid (JA), jasmonate-isoleucine (JA-Ile) and methyl jasmonate (MeJA) were strongly correlated with theanine content; IAA, GA1 and gibberellin 4 (GA4) were significantly correlated with caffeine content at different temperatures. In order to explore the internal intricate relationships between the biosynthesis of these three main taste components, endogenous hormones, and structural genes in tea plants, we used multi-omics and multidimensional correlation analysis to speculate the regulatory mechanisms: IAA, GA1 and GA3 up-regulated the expressions of chalcone synthase (CsCHS) and trans-cinnamate 4-monooxygenase (CsC4H) mediated by the signal transduction factors auxin-responsive protein IAA (CsIAA) and DELLA protein (CsDELLA), respectively, which promoted the biosynthesis of EGCG; IAA, GA3 and GA1 up-regulated the expression of CsCHS and anthocyanidin synthase (CsANS) mediated by CsIAA and CsDELLA, respectively, via the transcription factor WRKY DNA-binding protein (CsWRKY), and promoted the biosynthesis of EGCG; JA, JA-Ile and MeJA jointly up-regulated the expression of carbonic anhydrase (CsCA) and down-regulated the expression of glutamate decarboxylase (CsgadB) mediated by the signal transduction factors jasmonate ZIM domain-containing protein (CsJAZ), and promoted the biosynthesis of theanine; JA, JA-Ile and MeJA also jointly inhibited the expression of CsgadB mediated by CsJAZ via the transcription factor CsWRKY and AP2 family protein (CsAP2), which promoted the biosynthesis of theanine; IAA inhibited the expression of adenylosuccinate synthase (CspurA) mediated by CsIAA via the transcription factor CsWRKY; GA1 and gibberellin 4 (GA4) inhibited the expression of CspurA mediated by CsDELLA through the transcription factor CsWRKY, which promoted the biosynthesis of caffeine. In conclusion, we revealed the underlying mechanism of the biosynthesis of the main taste components in tea plant in response to temperature was mediated by hormone signal transduction factors, which provided novel insights into improving the quality of tea.

Research progress on negative pressure wound therapy with instillation in the treatment of orthopaedic wounds.

Negative pressure wound therapy with instillation (NPWTi) has the dual function of negative pressure sealing drainage and irrigation, which overcomes the disadvantages of NPWT, such as tube obstruction, inability to apply topical medicine, and poor anti-infection ability. NPWTi has been researched extensively and widely used in various types of wounds, and certain effects have been achieved. A series of parameters for NPWTi have not been unified at present, including the flushing fluid option, flushing mode, and treatment period. This paper reviews the research progress of these parameters for NPWTi and their application in the treatment of orthopaedic wounds.

The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPARγ in Xenopus tropicalis.

The RXR agonist (triphenyltin, TPT) and the RXR antagonist (UVI3003) both show teratogenicity and, unexpectedly, induce similar malformations in Xenopus tropicalis embryos. In the present study, we exposed X. tropicalis embryos to UVI3003 in seven specific developmental windows and identified changes in gene expression. We further measured the ability of UVI3003 to activate Xenopus RXRα (xRXRα) and PPARγ (xPPARγ) in vitro and in vivo. We found that UVI3003 activated xPPARγ either in Cos7 cells (in vitro) or Xenopus embryos (in vivo). UVI3003 did not significantly activate human or mouse PPARγ in vitro; therefore, the activation of Xenopus PPARγ by UVI3003 is novel. The ability of UVI3003 to activate xPPARγ explains why UVI3003 and TPT yield similar phenotypes in Xenopus embryos. Our results indicate that activating PPARγ leads to teratogenic effects in Xenopus embryos. More generally, we infer that chemicals known to specifically modulate mammalian nuclear hormone receptors cannot be assumed to have the same activity in non-mammalian species, such as Xenopus. Rather they must be tested for activity and specificity on receptors of the species in question to avoid making inappropriate conclusions.

An assay to determine the sensitive window of embryos to chemical exposure using Xenopus tropicalis.

The frog embryo teratogenesis assay-Xenopus (FETAX) is an established method to evaluate the developmental toxicity of chemicals. In FETAX, a 48 h continuous exposure is usually conducted when the X. tropicalis embryo is used as the test model. In the present study, we exposed X. tropicalis embryos to nine known teratogens for four separate 12-h periods. The embryos showed great variations in response to nine tested compounds during different exposure periods. Based on the value of the score of malformations, the most sensitive 12 h exposure periods of embryos were significantly distinguished for all the compounds with the exception of NiCl2 . The embryos were the most sensitive to retinols (e.g. all-trans-retinoic acid and 9-cis-retinoic acid) during 0-12 h and to metal compounds (e.g. triphenlytin and CdCl2) during a 24 to 36 h exposure period. In the further 3 h exposure experiment, the most sensitive period could only be determined for one of three tested compounds. Based on the present results, we proposed an assay to determine a 12 h sensitive window of embryos to chemical exposure using Xenopus tropicalis.

Use of the enhanced frog embryo teratogenesis assay-Xenopus (FETAX) to determine chemically-induced phenotypic effects.

The frog embryo teratogenesis assay-Xenopus (FETAX) is an established method for the evaluation of the developmental toxicities of chemicals. To develop an enhanced FETAX that is appropriate for common environmental contaminants, we exposed Xenopus tropicalis embryos to eight compounds, including tributyltin, triphenyltin, CdCl2, pyraclostrobin, picoxystrobin, coumoxystrobin, all-trans-retinoic acid and 9-cis-retinoic acid. Multiple malformations were induced in embryos particularly following exposure to tributyltin, triphenyltin and pyraclostrobin at environmentally relevant concentrations. Based on the range of observed malformations, we proposed a phenotypic assessment method with 20 phenotypes and a 0-5 scoring system. This derived index exhibited concentration-dependent relationships for all of the chemicals tested. Furthermore, the phenotype profiles were characteristic of the different tested chemicals. Our results indicate that malformation phenotypes can be quantitatively integrated with the primary endpoints in conventional FETAX assessments to allow for increased sensitivity and measurement of quantitative effects and to provide indicative mechanistic information for each tested chemical.

Unexpected phenotypes of malformations induced in Xenopus tropicalis embryos by combined exposure to triphenyltin and 9-cis-retinoic acid.

Xenopus tropicalis embryos were exposed for 48 hr to the mixtures of 5 µg Sn/L triphenyltin (TPT), which is a well-known endocrine disruptor, and 0.25-5 µg/L 9-cis retinoic acid (9c-RA), which is the natural ligand of retinoid X receptor. The phenotypes induced by combined exposure were more variable than those resulting from single exposure to either TPT or 9c-RA. The prominent phenotypes included underdeveloped head structures, abnormal eyes, narrow fins, enlarged proctodaeum, etc. Especially, combined exposure induced unexpected notochord malformations, which ranged from small swellings of the surface of the tails to the extension and extrusion of notochord out of the posterior tails. Compared with the 5 µg Sn/L TPT-treated group, the index of fin deficiency was not affected, and the index of axis deficiency was significantly increased with increasing RA concentrations in the mixtures. Our results suggest that combined exposure to TPT and 9c-RA induced not only more variable phenotypes of malformations than exposure to single compound but also some new and unexpected phenotypes.

Effects of antagonist of retinoid X receptor (UVI3003) on morphology and gene profile of Xenopus tropicalis embryos.

We exposed Xenopus tropicalis embryos to a selective antagonist of retinoid X receptor (UVI3003). UVI3003 induced multiple malformations at the concentrations of 200-1000 µg/L after 48 h exposure. The most prominent malformations affected brains, eyes, cement gland and fins. UVI3003 also induced variable and divergent malformations at 250-1500 µg/L after 0-24 and 24-48 h exposure. Microarray analysis showed that seven genes (rps15, serp2, fmr1, cyp2e1, lrrc9, ugtla6 and LOC100490188) were differentially regulated in all three treatment groups after 0-24h exposure. The most significantly affected pathway was galactose metabolism. In 24-48 h exposure groups, 18 genes were differentially regulated, mainly comprising components of the PPAR signaling pathway. These results suggested that UVI3003 is teratogenic in amphibian embryos. Differential gene expression suggests that galactose metabolism and PPAR signaling pathways may provide underlying mechanistic detail accounting for the observed malformations.