Celastrol mediates CAV1 to attenuate pro-tumorigenic effects of senescent cells.

BACKGROUND: Cellular senescence is an emerging hallmark of cancers, primarily fuels cancer progression by expressing senescence-associated secretory phenotype (SASP). Caveolin-1 (CAV1) is a key mediator of cell senescence. Previous studies from our group have evidenced that the expression of CAV1 is downregulated by Celastrol (CeT). PURPOSE: To investigate the impact of CeT on cellular senescence and its subsequent influence on post-senescence-driven invasion, migration, and stemness of clear cell renal cell carcinoma (ccRCC). STUDY DESIGN AND METHODS: The expression levels of CAV1, canonical senescence markers, and markers associated with epithelial-mesenchymal transition (EMT) and stemness in clinical samples were assessed through Pearson correlation analysis. Senescent cell models were induced using DOX, and their impact on migration, invasion, and stemness was evaluated. The effects of CeT treatment on senescent cells and their pro-tumorigenic effects were examined. Subsequently, the underlying mechanism of CeT were explored using lentivirus transfection and CRISPR/Cas9 technology to silence CAV1. RESULTS: In human ccRCC clinical samples, the expression of the canonical senescence markers p53, p21, and p16 are associated with ccRCC progression. Senescent cells facilitated migration, invasion, and enhanced stemness in both ccRCC cells and ccRCC tumor-bearing mice. As expected, CeT treatment reduced senescence markers (p16, p53, p21, SA-ß-gal) and SASP factors (IL6, IL8, CXCL12), alleviating cell cycle arrest. However, it did not restore the proliferation of senescent cells. Additionally, CeT suppressed senescence-driven migration, invasion, and stemness. Further investigations into the underlying mechanism demonstrated that CAV1 is a critical mediator of cell senescence and represents a potential target for CeT to attenuate cellular senescence. CONCLUSIONS: This study presents a pioneering investigation into the intricate interplay between cellular senescence and ccRCC progression. We unveil a novel mechanism of CeT to mitigate cellular senescence by downregulating CAV1, thereby inhibiting the migration, invasion and stemness of ccRCC driven by senescent cells. These findings provide valuable insights into the underlying mechanisms of CeT and its potential as a targeted therapeutic approach for alleviating the aggressive phenotypes associated with senescent cells in ccRCC.

Lipids and lipid metabolism in cellular senescence: Emerging targets for age-related diseases.

Cellular senescence is a kind of cellular state triggered by endogenous or exogenous stimuli, which is mainly characterized by stable cell cycle arrest and complex senescence-associated secretory phenotype (SASP). Once senescent cells accumulate in tissues, they may eventually accelerate the progression of age-related diseases, such as atherosclerosis, osteoarthritis, chronic lung diseases, cancers, etc. Recent studies have shown that the disorders of lipid metabolism are not only related to age-related diseases, but also regulate the cellular senescence process. Based on existing research evidences, the changes in lipid metabolism in senescent cells are mainly concentrated in the metabolic processes of phospholipids, fatty acids and cholesterol. Obviously, the changes in lipid-metabolizing enzymes and proteins involved in these pathways play a critical role in senescence. However, the link between cellular senescence, changes in lipid metabolism and age-related disease remains to be elucidated. Herein, we summarize the lipid metabolism changes in senescent cells, especially the senescent cells that promote age-related diseases, as well as focusing on the role of lipid-related enzymes or proteins in senescence. Finally, we explore the prospect of lipids in cellular senescence and their potential as drug targets for preventing and delaying age-related diseases.

Celastrol Elicits Antitumor Effects through Inducing Immunogenic Cell Death and Downregulating PD-L1 in ccRCC.

BACKGROUND: Targeting immunogenic cell death (ICD) is considered a promising therapeutic strategy for cancer. However, the commonly identified ICD inducers promote the expression of programmed cell death ligand 1 (PD-L1) in tumor cells, thus aiding them to evade the recognition and killing by the immune system. Therefore, the finding of novel ICD inducers to avoid enhanced PD-L1 expression is of vital significance for cancer therapy. Celastrol (CeT), a triterpene isolated from Tripterygium wilfordii Hook. F induces various forms of cell death to exert anti-cancer effects, which may make celastrol an attractive candidate as an inducer of ICD. METHODS: In the present study, bioinformatics analysis was combined with experimental validation to explore the underlying mechanism by which CeT induces ICD and regulates PD-L1 expression in clear cell renal cell carcinoma (ccRCC). RESULTS: The results showed that EGFR, IKBKB, PRKCQ and MAPK1 were the crucial targets for CeT-induced ICD, and only MAPK1 was an independent prognostic factor for the overall survival (OS) of ccRCC patients. In addition, CeT triggered autophagy and up-regulated the expressions of HMGB1 and CRT to induce ICD in 786-O cells in vitro. Importantly, CeT can down-regulate PD-L1 expression through activating autophagy. At the molecular level, CeT suppressed PD-L1 via the inhibition of MAPK1 expression. Immunologically, the core target of celastrol, MAPK1, was tightly correlated with CD8+ T cells and CD4+ T cells in ccRCC. CONCLUSION: These findings indicate that CeT not only induces ICD but also suppresses PD-L1 by down-regulating MAPK1 expression, which will provide an attractive strategy for ccRCC immunotherapy.

Roles of Cyt-c/Caspase-9/Caspase-3/Bax/Bcl-2 pathway in Cd-induced testicular injury in rats and the protective effect of quercetin.

Cadmium (Cd) exposure causes oxidative damage to mitochondria, which would adversely affect rat testicular tissue. Quercetin (Que) is a natural antioxidant with anti-inflammatory, antioxidant and anti-apoptotic effects. However, the mechanism by which Que inhibits Cd-induced apoptosis of testicular cells remains unclear. The purpose of this study was to investigate the role of mitochondrial apoptosis pathway (Cyt-c/Caspase-9/Caspase-3/Bax/Bcl-2 pathway) in inhibiting Cd-induced apoptosis of testicular cells by Que. We used SD rats to simulate Cd chloride exposure by treating all sides of the rats with CdCl2 and/or Que. The levels of GSH and MDA in rat testis were detected using reagent kits. The effects of CdCl2 and/or Que on tissue damage, apoptosis, and gene and protein expression of the Cyt-c/Caspase-9/Caspase-3/Bax/Bcl-2 pathway in rat testis were examined by HE, TUNEL, RNA extraction and reverse-transcriptase polymerase chain reaction (RT-PCR), and Western blot (Wb). The results show that Cd significantly increased the contents of GSH and MDA in rat testis (P < 0.01); conversely, Que significantly reduced the contents of GSH and MDA (P < 0.01). Cd inflicted damage to testicular tissue, and Que addition significantly reduced the damage. Cd increased the number of apoptosis of testicle cells, and Que inhibited testicle-cell apoptosis. In addition, the results of reverse transcription PCR and Wb assays confirmed that, as expected, Cd increased the expression levels of Cyt-c, Caspase-9, Caspase-3, and Bax mRNAs as well as proteins. And at the same time decreased the expression of the anti-apoptotic factor Bcl-2 in the cells. Surprisingly, these effects were reversed when Que was added. Therefore, Que can play an antioxidant and anti-apoptotic role in reducing the testicular tissue damage caused by Cd exposure. This provides a conceptual basis for the later development and utilization of Que as well as the prevention and treatment of tissue damage caused by Cd exposure.

Enhancement of the carboxymethylation of corn starch via induced electric field.

This study aimed to enhance the synthesis of carboxymethyl starch (CMS) by induced electric field (IEF). Corn starch was alkalized, pumped into IEF system, and then reacted with monochloroacetic acid at excitation voltages of 0-400 V. IEF enhanced the carboxymethylation by accelerating the rate of OH- and ClCH2COO- attacking starch particles and slightly intensifying the thermal effect by ~7.1 °C (30 min). Compared with the control (0 V), IEF increased the degree of substitution and reaction efficiency by 0.056-0.148 and 9.37-24.56 %, caused more destruction in starch granular and crystal structure, and thus increased its water solubility, swelling power, and paste transparency. Furthermore, some new crystals were formed during IEF treatment, which enhanced the thermostability of CMS, showing an increase of the maximum decomposition temperature by 16-26 °C. Overall, the results classified that IEF could improve the carboxymethylation and enhance the thermostability of products, which provided guides for the applications of electro-techniques in starch modification involving charged species.

Mechanisms of dihydromyricetin against hepatocellular carcinoma elucidated by network pharmacology combined with experimental validation.

CONTEXT: Dihydromyricetin (DMY) is extracted from vine tea, a traditional Chinese herbal medicine with anti-cancer, liver protection, and cholesterol-lowering effects. OBJECTIVE: This study investigated the mechanism of DMY against hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Potential DMY, HCC, and cholesterol targets were collected from relevant databases. PPI networks were created by STRING. Then, the hub genes of co-targets, screened using CytoHubba. GO and KEGG pathway enrichment, were performed by Metascape. Based on the above results, a series of in vitro experiments were conducted by using 40-160 µM DMY for 24 h, including transwell migration/invasion assay, western blotting, and Bodipy stain assay. RESULTS: Network pharmacology identified 98 common targets and 10 hub genes of DMY, HCC, and cholesterol, and revealed that the anti-HCC effect of DMY may be related to the positive regulation of lipid rafts. Further experiments confirmed that DMY inhibits the proliferation, migration, and invasion of HCC cells and reduces their cholesterol levels in vitro. The IC50 is 894.4, 814.4, 467.8, 1,878.8, 151.8, and 156.9 µM for 97H, Hep3B, Sk-Hep1, SMMC-7721, HepG2, and Huh7 cells, respectively. In addition, DMY downregulates the expression of lipid raft markers (CAV1, FLOT1), as well as EGFR, PI3K, Akt, STAT3, and Erk. DISCUSSION AND CONCLUSION: The present study reveals that DMY suppresses EGFR and its downstream pathways by reducing cholesterol to disrupt lipid rafts, thereby inhibiting HCC, which provides a promising candidate drug with low toxicity for the treatment of HCC.

Celastrol functions as an emerging manager of lipid metabolism: Mechanism and therapeutic potential.

Lipid metabolism disorders are pivotal in the development of various lipid-related diseases, such as obesity, atherosclerosis, non-alcoholic fatty liver disease, type 2 diabetes, and cancer. Celastrol, a bioactive compound extracted from the Chinese herb Tripterygium wilfordii Hook F, has recently demonstrated potent lipid-regulating abilities and promising therapeutic effects for lipid-related diseases. There is substantial evidence indicating that celastrol can ameliorate lipid metabolism disorders by regulating lipid profiles and related metabolic processes, including lipid synthesis, catabolism, absorption, transport, and peroxidation. Even wild-type mice show augmented lipid metabolism after treatment with celastrol. This review aims to provide an overview of recent advancements in the lipid-regulating properties of celastrol, as well as to elucidate its underlying molecular mechanisms. Besides, potential strategies for targeted drug delivery and combination therapy are proposed to enhance the lipid-regulating effects of celastrol and avoid the limitations of its clinical application.

A Lipid Perspective on Regulated Pyroptosis.

Pyroptosis is a novel pro-inflammatory cell programmed death dependent on Gasdermin (GSMD) family-mediated membrane pore formation and subsequent cell lysis, accompanied by the release of inflammatory factors and expanding inflammation in multiple tissues. All of these processes have impacts on a variety of metabolic disorders. Dysregulation of lipid metabolism is one of the most prominent metabolic alterations in many diseases, including the liver, cardiovascular system, and autoimmune diseases. Lipid metabolism produces many bioactive lipid molecules, which are important triggers and endogenous regulators of pyroptosis. Bioactive lipid molecules promote pyroptosis through intrinsic pathways involving reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, lysosomal disruption, and the expression of related molecules. Pyroptosis can also be regulated during the processes of lipid metabolism, including lipid uptake and transport, de novo synthesis, lipid storage, and lipid peroxidation. Taken together, understanding the correlation between lipid molecules such as cholesterol and fatty acids and pyroptosis during metabolic processes can help to gain insight into the pathogenesis of many diseases and develop effective strategies from the perspective of pyroptosis.

GSH-specific fluorescent probe for sensing, bioimaging, rapid screening of natural inhibitor Celastrol and ccRCC theranostics.

High level of intracellular glutathione (GSH) has been identified as a major barrier for cancer therapy. Therefore, effective regulation of GSH can be regarded as a novel approach for cancer therapy. In this study, an off-on fluorescent probe (NBD-P) is developed for selective and sensitive sensing GSH. NBD-P has a good cell membrane permeability that can be applied in bioimaging endogenous GSH in living cells. Moreover, the NBD-P probe is used to visualize GSH in animal models. In addition, a rapid drug screening method is successfully established using the fluorescent probe NBD-P. A potent natural inhibitor of GSH is identified as Celastrol from Tripterygium wilfordii Hook F, which effectively triggers mitochondrial apoptosis in clear cell renal cell carcinoma (ccRCC). More importantly, NBD-P can selectively respond to GSH fluctuations to distinguish cancer tissues from normal tissues. Thus, the present study provides insights into fluorescence probes for the screening GSH inhibitors and cancer diagnosis, as well as in-depth exploration of the anti-cancer effects of Traditional Chinese Medicine (TCM).

Resistin-like molecules: a marker, mediator and therapeutic target for multiple diseases.

Resistin-like molecules (RELMs) are highly cysteine-rich proteins, including RELMα, RELMß, Resistin, and RELMγ. However, RELMs exhibit significant differences in structure, distribution, and function. The expression of RELMs is regulated by various signaling molecules, such as IL-4, IL-13, and their receptors. In addition, RELMs can mediate numerous signaling pathways, including HMGB1/RAGE, IL-4/IL-4Rα, PI3K/Akt/mTOR signaling pathways, and so on. RELMs proteins are involved in wide range of physiological and pathological processes, including inflammatory response, cell proliferation, glucose metabolism, barrier defense, etc., and participate in the progression of numerous diseases such as lung diseases, intestinal diseases, cardiovascular diseases, and cancers. Meanwhile, RELMs can serve as biomarkers, risk predictors, and therapeutic targets for these diseases. An in-depth understanding of the role of RELMs may provide novel targets or strategies for the treatment and prevention of related diseases. Video abstract.

MiR-140 is involved in T-2 toxin-induced matrix degradation of articular cartilage.

T-2 toxin is one of the most toxic mycotoxins contaminating various grains. It is considered an environmental risk factor for Kashin-Beck disease (KBD), an endemic degenerative osteochondrosis. Currently, the underlying molecular mechanisms of articular cartilage damage caused by T-2 toxin have not been elucidated. Studies have shown that miR-140 is essential for cartilage formation, and extracellular matrix (EMC) synthesis and degradation. The objective of this study was to investigate the mechanism of miR-140 involvement in T-2 toxin-induced articular cartilage damage. Two treatment groups, each containing wild-type mice and miR-140 knockout mice were administered with T-2 toxin (200 ng/g BW/day) or a normal diet for 1 month, 3 months, and 6 months. Results showed that T-2 toxin caused articular cartilage and growth plate damage in mice. The expression of miR-140 decreased in articular cartilage of wild-type mice treated with T-2 toxin, and miR-140 deficiency aggravated T-2 toxin-induced knee cartilage damage. T-2 toxin-caused the reduction of miR-140 expression was consistent with collagen type II (COL2A1), aggrecan (ACAN), and SRY-box containing gene 9 (SOX9) and opposite to matrix metalloproteinase 13 (MMP13), a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), and v-ral simian leukemia viral oncogene homolog A (RALA). In addition, we collected finger joints cartilage and knee joints cartilage from KBD patients and controls for paraffin embedding and sectioning. Results found that the expression of miR-140 in the articular cartilage of the KBD group was lower than that of the control group. The expression of COL2A1, ACAN, and SOX9 decreased, whereas ADAMTS-5, MMP13, and RALA increased in the articular cartilage of the KBD group. These results revealed that miR-140 might be involved in T-2 toxin-induced degradation of the ECM of articular cartilage. Moreover, the occurrence of KBD might be related to the decreased expression of miR-140 in articular cartilage.

Sanguinarine protects against indomethacin-induced small intestine injury in rats by regulating the Nrf2/NF-κB pathways.

In recent years, small intestine as a key target in the treatment of Inflammatory bowel disease caused by NSAIDs has become a hot topic. Sanguinarine (SA) is one of the main alkaloids in the Macleaya cordata extracts with strong pharmacological activity of anti-tumor, anti-inflammation and anti-oxidant. SA is reported to inhibit acetic acid-induced colitis, but it is unknown whether SA can relieve NSAIDs-induced small intestinal inflammation. Herein, we report that SA effectively reversed the inflammatory lesions induced by indomethacin (Indo) in rat small intestine and IEC-6 cells in culture. Our results showed that SA significantly relieved the symptoms and reversed the inflammatory lesions of Indo as shown in alleviation of inflammation and improvement of colon macroscopic damage index (CMDI) and tissue damage index (TDI) scores. SA decreased the levels of TNF-α, IL-6, IL-1ß, MDA and LDH in small intestinal tissues and IEC-6 cells, but increased SOD activity and ZO-1 expression. Mechanistically, SA dose-dependently promoted the expression of Nrf2 and HO-1 by decreasing Keap-1 level, but inhibited p65 phosphorylation and nuclear translocation in Indo-treated rat small intestine and IEC-6 cells. Furthermore, in SA treated cells, the colocalization between p-p65 and CBP in the nucleus was decreased, while the colocalization between Nrf2 and CBP was increased, leading to the movement of gene expression in the nucleus to the direction of anti-inflammation and anti-oxidation. Nrf2 silencing blocked the effects of SA. Together our results suggest that SA can significantly prevent intestinal inflammatory lesions induced by Indo in rats and IEC-6 cells through regulation of the Nrf2 pathway and NF-κBp65 pathway.

Wnt5a/Ror2 promotes vascular smooth muscle cells proliferation via activating PKC.

INTRODUCTION: Abnormal proliferation of vascular smooth muscle cells (VSMCs) can cause various vascular diseases, such as atherosclerosis, restenosis, and pulmonary hypertension. However, the effect and underlying mechanism of Wnt5a on the proliferation of VSMCs remain unclear. Our study aimed to investigate whether Wnt5a/Ror2 promotes vascular smooth muscle cell proliferation via activating protein kinase C (PKC), thereby effectively alleviating vascular proliferative diseases. MATERIAL AND METHODS: The proliferation of HA-VSMC cell line was evaluated by CCK-8, EdU, and Plate clone formation assays. The Wnt5a gene knockdown and overexpression were carried out by standard methods. The interaction between Wnt5a and Ror2 was explored by co-immunoprecipitation. Western blotting and immunofluorescence were used to determine the expression levels of key proteins in VSMCs. RESULTS: The present study found that the expression of Wnt5a protein increased significantly in the proliferation of VSMCs stimulated by 10% serum in a time-dependent manner. Furthermore, the proliferative rate of VSMCs overexpressing Wnt5a was dramatically accelerated, whereas Wnt5a knockdown using siWnt5a reversed thisproliferative effect. Wnt5a up-regulated the expression of receptor tyrosine kinase-like orphan receptor 2 (Ror2) by binding to it. Further studies indicated that Wnt5a induces the PKC expression in VSMCs and knockdown of Wnt5a or Ror2 could inhibit PKC phosphorylation. CONCLUSIONS: Wnt5a could effectively promote the proliferation of VSMCs, which might be related to the binding of Wnt5a and Ror2 to activate PKC.

New dawn for cancer cell death: Emerging role of lipid metabolism.

BACKGROUND: Resistance to cell death, a protective mechanism for removing damaged cells, is a "Hallmark of Cancer" that is essential for cancer progression. Increasing attention to cancer lipid metabolism has revealed a number of pathways that induce cancer cell death. SCOPE OF REVIEW: We summarize emerging concepts regarding lipid metabolic reprogramming in cancer that is mainly involved in lipid uptake and trafficking, de novo synthesis and esterification, fatty acid synthesis and oxidation, lipogenesis, and lipolysis. During carcinogenesis and progression, continuous metabolic adaptations are co-opted by cancer cells, to maximize their fitness to the ever-changing environmental. Lipid metabolism and the epigenetic modifying enzymes interact in a bidirectional manner which involves regulating cancer cell death. Moreover, lipids in the tumor microenvironment play unique roles beyond metabolic requirements that promote cancer progression. Finally, we posit potential therapeutic strategies targeting lipid metabolism to improve treatment efficacy and survival of cancer patient. MAJOR CONCLUSIONS: The profound comprehension of past findings, current trends, and future research directions on resistance to cancer cell death will facilitate the development of novel therapeutic strategies targeting the lipid metabolism.

Development of dendrimer-like glucan-stabilized Pickering emulsions incorporated with ß-carotene.

The impact of sugary maize dendrimer-like glucan octenyl succinate (OSA-SMDG) on the storage stability and antioxidant activity of ß-carotene (BC)-loaded emulsions as well as bioaccessibility were investigated. The encapsulation efficiency of ß-carotene in emulsions containing 3% OSA-SMDG (3OSA-SMDG-BC) or 5% OSA-SMDG (5OSA-SMDG-BC) was 89.6% and 94.9%, respectively. The antioxidant activity of both emulsions was higher than that of pure ß-carotene. During simulated digestion, the particle size of emulsions was immediately reduced, whereas zeta-potential was continuously increased in intestinal digestion. After 2 h digestion, the free fatty acids (FFA) release rate of 3OSA-SMDG-BC and 5OSA-SMDG-BC was significantly higher than that of blank emulsion. Bioaccessibility of ß-carotene encapsulated in 3OSA-SMDG-BC and 5OSA-SMDG-BC was also significantly higher than that of blank emulsion. FFA release rate and ß-carotene bioaccessibility of 5OSA-SMDG-BC were higher than that of 3OSA-SMDG-BC. These results demonstrated that OSA-SMDG could be used to fabricate food-grade O/W Pickering emulsion as a delivery system for bioactive compounds.

Avian Eggshell Membrane as a Novel Biomaterial: A Review.

The eggshell membrane (ESM), mainly composed of collagen-like proteins, is readily available as a waste product of the egg industry. As a novel biomaterial, ESM is attractive for its applications in the nutraceutical, cosmetic, and pharmaceutical fields. This review provides the main information about the structure and chemical composition of the ESM as well as some approaches for its isolation and solubilization. In addition, the review focuses on the role and performance of bioactive ESM-derived products in various applications, while a detailed literature survey is provided. The evaluation of the safety of ESM is also summarized. Finally, new perspectives regarding the potential of ESM as a novel biomaterial in various engineering fields are discussed. This review provides promising future directions for comprehensive application of ESM.

Celastrol ameliorates vascular neointimal hyperplasia through Wnt5a-involved autophagy.

Neointimal hyperplasia caused by the excessive proliferation of vascular smooth muscle cells (VSMCs) is the pathological basis of restenosis. However, there are few effective strategies to prevent restenosis. Celastrol, a pentacyclic triterpene, has been recently documented to be beneficial to certain cardiovascular diseases. Based on its significant effect on autophagy, we proposed that celastrol could attenuate restenosis through enhancing autophagy of VSMCs. In the present study, we found that celastrol effectively inhibited the intimal hyperplasia and hyperproliferation of VSMCs by inducing autophagy. It was revealed that autophagy promoted by celastrol could induce the lysosomal degradation of c-MYC, which might be a possible mechanism contributing to the reduction of VSMCs proliferation. The Wnt5a/PKC/mTOR signaling pathway was found to be an underlying mechanism for celastrol to induce autophagy and inhibit the VSMCs proliferation. These observations indicate that celastrol may be a novel drug with a great potential to prevent restenosis.

Targeting HDL in tumor microenvironment: New hope for cancer therapy.

Epidemiological studies have shown that plasma HDL-C levels are closely related to the risk of prostate cancer, breast cancer, and other malignancies. As one of the key carriers of cholesterol regulation, high-density lipoprotein (HDL) plays an important role in tumorigenesis and cancer development through anti-inflammation, antioxidation, immune-modulation, and mediating cholesterol transportation in cancer cells and noncancer cells. In addition, the occurrence and progression of cancer are closely related to the alteration of the tumor microenvironment (TME). Cancer cells synthesize and secrete a variety of cytokines and other factors to promote the reprogramming of surrounding cells and shape the microenvironment suitable for cancer survival. By analyzing the effect of HDL on the infiltrating immune cells in the TME, as well as the relationship between HDL and tumor-associated angiogenesis, it is suggested that a moderate increase in the level of HDL in vivo with consequent improvement of the function of HDL in the TME and induction of intracellular cholesterol efflux may be a promising strategy for cancer therapy.

Extraction, isolation, characterization and antimicrobial activities of non-extractable polyphenols from pomegranate peel.

Non-extractable polyphenols (NEPPs) in pomegranate peel were released by acid hydrolysis followed by extraction using ethyl acetate (EtOAc). Ten NEPPs were identified in the hydrolysate using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Six compounds were then isolated from the EtOAc extracts whose structures were identified as ß-sitosterol-3-O-glycoside (1), ß-sitosterol (2), ursolic acid (3), corosolic acid (4), asiatic acid (5) and arjunolic acid (6) using a wide range of spectroscopic analyses. Compounds 4-6 were isolated for the first time from pomegranate peel. Antimicrobial experiments revealed that compound 3 and 5 showed significant antimicrobial activity against a range of pathogens, particularly compound 5 which exhibited selective inhibitive activity towards Staphylococcus aureus with a minimum inhibitory concentration (MIC) of 16 µg/ml. The present study has provided new insights into the composition of bound chemicals in pomegranate peel and laid a foundation for improving its further processing and utilization.

PVAT targets VSMCs to regulate vascular remodelling: angel or demon.

Vascular remodelling refers to abnormal changes in the structure and function of blood vessel walls caused by injury, and is the main pathological basis of cardiovascular diseases such as atherosclerosis, hypertension, and pulmonary hypertension. Among them, the neointimal hyperplasia caused by abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a key role in the pathogenesis of vascular remodelling. Perivascular adipose tissue (PVAT) can release vasoactive substances to target VSMCs and regulate the pathological process of vascular remodelling. Specifically, PVAT can promote the conversion of VSMCs phenotype from contraction to synthesis by secreting visfatin, leptin, and resistin, and participate in the development of vascular remodelling-related diseases. Conversely, it can also inhibit the growth of VSMCs by secreting adiponectin and omentin to prevent neointimal hyperplasia and alleviate vascular remodelling. Therefore, exploring and developing new drugs or other treatments that facilitate the beneficial effects of PVAT on VSMCs is a potential strategy for prevention or treatment of vascular remodelling-related cardiovascular diseases.