Untargeted metabolomics reveals the regulatory effect of geniposidic acid on lipid accumulation in HepG2 cells and Caenorhabditis elegans and validation in hyperlipidemic hamsters.

BACKGROUND: Geniposidic acid (GPA) alleviates oxidative stress and inflammation in mice However, whether it can effectively regulate lipid accumulation and prevent hyperlipidemia requires further investigation. PURPOSE: This study combined the untargeted metabolomics of cells and a Caenorhabditis elegans model to evaluate the anti-hyperlipidemic potential of GPA by modulating oxidative stress and regulating lipid metabolism. A golden hamster model of hyperlipidemia was used to further validate the lipid-lowering effect and mechanism of action of GPA. METHODS: Chemical staining, immunofluorescence, and flow cytometry were performed to examine the effects of GPA on lipid accumulation and oxidative stress. Untargeted metabolomic analysis of cells and C. elegans was performed using ultra-performance liquid chromatography coupled with quadrupole electrostatic field Orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap MS) to identify biomarkers altered by GPA action, analyze the affected metabolic pathways, and validate the mechanisms by which GPA regulates lipid metabolism and oxidative stress. A golden hamster model of hyperlipidemia was established to test the lipid-lowering effects of GPA. Body weight, biochemical markers, rate-limiting enzymes, and key proteins were assessed. Hematoxylin and eosin (H&E) and Oil Red O staining were performed. RESULTS: Phenotypic data showed that GPA decreased free fatty acid (FFA)-induced lipid buildup and high reactive oxygen species (ROS) levels, reversed the decrease in mitochondrial membrane potential (MMP), and increased the cellular reduced glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio. GPA also reduces high glucose-induced lipid build-up and ROS production in C. elegans. Metabolomic analysis showed that GPA affected purine, lipid, and amino acid metabolism. Moreover, GPA inhibited xanthine oxidase (XOD), glutamate dehydrogenase (GLDH), fatty acid synthase (FAS), phosphorylation of P38 MAPK, and upregulated the expression of SIRT3 and CPT1A protein production to control lipid metabolism and produce antioxidant benefits in cells and golden hamsters. CONCLUSION: Current evidence suggests that GPA can effectively regulate lipid metabolism and the oxidative stress response, and has the potential to prevent hyperlipidemia. This study also provided an effective method for evaluating the mechanism of action of GPA.

A Streptomyces species from the ginseng rhizosphere exhibits biocontrol potential.

Plants and their associated microbes live in complicated, changeable, and unpredictable environments. They usually interact with each other in many ways through multidimensional, multiscale, and multilevel coupling manners, leading to challenges in the coexistence of randomness and determinism or continuity and discreteness. Gaining a deeper understanding of these diverse interaction mechanisms can facilitate the development of data-mining theories and methods for complex systems, coupled modeling for systems with different spatiotemporal scales and functional properties, or even a universal theory of information and information interactions. In this study, we use a "closed-loop" model to present a plant-microbe interaction system and describe the probable functions of microbial natural products. Specifically, we report a rhizosphere species, Streptomyces ginsengnesis G7, which produces polyketide lydicamycins and other active metabolites. Interestingly, these distinct molecules have the potential to function both as antibiotics and as herbicides for crop protection. Detailed laboratory experiments conducted in Arabidopsis (Arabidopsis thaliana), combined with a comprehensive bioinformatics analysis, allow us to rationalize a model for this specific plant-microbe interaction process. Our work reveals the benefits of exploring otherwise neglected resources for the identification of potential functional molecules and provides a reference to better understand the system biology of complex ecosystems.

Discussion on the mechanism of Lingguizhugan Decoction in treating hypertension based on network pharmacology and molecular simulation technology.

To explore the mechanism of Lingguizhugan Decoction in treating hypertension based on network pharmacology and molecular simulation. The active ingredients and potential targets were screened by the Systematic Pharmacological Analysis Platform of Traditional Chinese Medicine (TCMSP). Hypertension-related targets were obtained from OMIM and GeneCards databases. Common targets between drug and hypertension were screened in the Venny platform. A protein-protein interaction (PPI) network was constructed in the STRING database using intersection targets. Key targets in PPI network were analyzed by Cytoscape. R language program was used for Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, the binding abilities of the main active ingredients to critical targets were verified by molecular simulation. Naringenin, quercetin, kaempferol, and ß-sitosterol in Lingguizhugan Decoction, and potential targets such as STAT3, AKT1, TNF, IL6, JUN, PTGS2, MMP9, CASP3, TP53, and MAPK3, were screened out. KEGG Enrichment analysis revealed that the common targets of Lingguizhugan Decoction and hypertension are mainly involved in the lipid and atherosclerosis signaling pathway, AGE-RAGE signaling pathway in diabetic complications, fluid shear stress and atherosclerosis, and IL17 signaling pathway. The molecular simulation results showed that naringenin-MAPK3, quercetin-MMP9, quercetin-PTGS2, and quercetin-TP53 were the top four in the docking scores. Naringenin-MAPK3 and quercetin-MMP9 were stable, with binding free energies of -27.97 ± 1.41 kcal/mol and -21.15 ± 3.17 kcal/mol, respectively. The possible mechanism of Lingguizhugan Decoction in treating hypertension is characterized of multi-component, multi-target, and multi-pathway.Communicated by Ramaswamy H. Sarma.

The synergistic effect of full-spectrum light therapy and transient immunosuppressants prolonged allotransplant survival.

BACKGROUND: The lifelong administration of immunosuppressants remains its largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model. METHODS: Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term anti-lymphocyte serum and cyclosporine-A. Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis. RESULTS: The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared to the control (group 1). However, group 4 with FBLT combined with short-term ALS/CsA significantly prolonged median composite tissue allograft survival time (266 days) compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) (p<0.01). Group 4 also showed a significant increase in Treg cells (p = 0.04) and TGF-ß1 levels (p = 0.02), and a trend toward a decrease in IL-1ß levels (p = 0.03) at 16 weeks after transplantation as compared to control Group 1. CONCLUSIONS: FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and anti-inflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival.

Triterpene acids from Rosa roxburghii Tratt fruits exert anti-hepatocellular carcinoma activity via ROS/JNK signaling pathway-mediated cell cycle arrest and mitochondrial apoptosis.

BACKGROUND: Rosa roxburghii Tratt (RRT) is a famous healthy and medicinal edible fruit in southwest China and has been shown to have some hepatoprotective properties. However, whether the active components, such as the triterpene acids from Rosa roxburghii Tratt fruits (TAR), have anti-hepatocellular carcinoma (HCC) effects and the potential molecular mechanisms are still unclear. PURPOSE: This study aimed to investigate the anti-HCC effects and potential action mechanisms of triterpene components in RRT fruits. METHODS: The triterpene acids in TAR were analyzed by using UPLC-Q-Exactive Orbitrap/MS, and the main components were virtual screening for targets based on pharmacophore and then performed enrichment analysis. HepG2 cells were used for in vitro experiments, including MTT assay, wound healing assay, and flow cytometry to detect cell cycle, reactive oxygen species (ROS) level, caspase-3 activity, and mitochondrial membrane potential (MMP) changes. Moreover, the western blot was used to detect mitochondrial apoptosis and ROS/ c-Jun N-terminal kinase (JNK) signaling pathway-related proteins. RESULTS: The main components in TAR are pentacyclic triterpene acids (mainly euscaphic acid and roxburic acid). TAR could inhibit cell viability, cell migration ability and suppress the proliferation of HepG2 cells through G2/M cell cycle arrest. On the other hand, TAR could induce HepG2 cells apoptosis, which was achieved by causing the accumulation of ROS and activation of the JNK signaling pathway, and our research showed that this apoptosis was mediated through the mitochondrial pathway. In addition, the free radical scavenger N-acetyl cysteine (NAC) could attenuate TAR-induced ROS accumulation and JNK signaling pathway activation, which ultimately reversed mitochondrial apoptosis. CONCLUSION: TAR could activate the ROS/JNK signaling pathway, which could inhibit the proliferation through G2/M cell cycle arrest and promote apoptosis through the mitochondrial pathway in HCC cells. This supports the anti-tumor potential in RRT fruits.

Identification of pancreatic lipase inhibitors from Eucommia ulmoides tea by affinity-ultrafiltration combined UPLC-Orbitrap MS and in vitro validation.

Pancreatic lipase inhibitors can reduce blood lipids by inactivating the catalytic activity of human pancreatic lipase, a key enzyme involved in triglyceride hydrolysis, which helps control some dyslipidemic diseases. The ability of Eucommia ulmoides tea to improve fat-related diseases is closely related to the natural inhibitory components of pancreatic lipase contained in the tea. In this study, fifteen pancreatic lipase inhibitors were screened and identified from Eucommia ulmoides tea by affinity-ultrafiltration combined UPLC-Q-Exactive Orbitrap/MS. Four representative components of geniposidic acid, quercetin-3-O-sambuboside, isochlorogenic acid A, and quercetin with high binding degrees were further verified by nanoscale differential scanning fluorimetry (nanoDSF) and enzyme inhibitory assays. The results of flow cytometry showed that they could significantly reduce the activity of pancreatic lipase in AR42J cells induced by palmitic acid in a concentration-dependent manner. Our findings suggest that Eucommia ulmoides tea may be a promising resource for pancreatic lipase inhibitors of natural origin.

Intelligent films of marine polysaccharides and purple cauliflower extract for food packaging and spoilage monitoring.

In this study, metalloanthocyanin-inspired, biodegradable packaging films were developed by incorporating purple cauliflower extracted (PCE) anthocyanins into alginate (AL)/carboxymethyl chitosan (CCS) hybrid polymer matrices based on complexation of metal ions with these marine polysaccharides and anthocyanins. PCE anthocyanins-incorporated AL/CCS films were further modified with fucoidan (FD) because this sulfated polysaccharide can form strong interactions with anthocyanins. Metals-involved complexation (Ca2+ and Zn2+-crosslinked films) improved the mechanical strength and water vapor permeability but reduced the swelling degree of the films. Zn2+-cross-linked films exhibited significantly higher antibacterial activity than did pristine (non-crosslinked) and Ca2+-cross-linked films. The metal ion/polysaccharide-involved complexation with anthocyanin reduced the release rate of anthocyanins, increased the storage stability and antioxidant capability, and improved the sensitivity of the colorimetric response of the indicator films for monitoring the freshness of shrimp. The anthocyanin-metal-polysaccharide complex film showed great potential as active and intelligent packaging of food products.

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma.

BACKGROUND: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC. METHODS: This was a large­scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC. RESULTS: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10- 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy. CONCLUSION: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients. TRIAL REGISTRATION NUMBER: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 .

Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1ß/KCC2 signaling during early development.

BACKGROUND: Neonatal sepsis can induce long-term cognitive impairment in adolescence or adulthood, but the underlying molecular mechanism is not fully understood. The expression of K+-Cl- co-transporter 2 (KCC2) plays a pivotal role in the GABAergic shift from depolarizing to hyperpolarizing during early postnatal development. In this study, we aimed to determine whether neonatal severe inflammation-induced cognitive impairment was associated with the expression of KCC2 during early development. METHODS: Neonatal severe inflammation was established by intraperitoneal injection of high dose lipopolysaccharide (LPS, 1 mg kg-1) in postnatal day 3 (P3) rats. The Morris water maze task and fear conditioning test were used to investigate long-term cognitive functions. ELISA, RT-PCR and Western blotting were used to examine the expression levels of proinflammatory cytokines and KCC2. Perforated patch-clamping recordings were used to determine the GABAergic shift. RESULTS: Neonatal severe inflammation led to long-term cognitive impairment in rats. Meanwhile, sustained elevation of interleukin-1 beta (IL-1ß) levels was found in the hippocampus until P30 after LPS injection. Elevated expression of KCC2 and hyperpolarized GABA reversal potential (EGABA) were observed in CA1 hippocampal pyramidal neurons from the P7-P10 and P14-P16 rats after LPS injection. Specific knockdown of IL-1ß mRNA expression rescued the elevated expression of KCC2 and the hyperpolarized EGABA at P7-P10 and P14-P16. Accordingly, specific knockdown of IL-1ß or KCC2 expression improved the cognitive impairment induced by neonatal severe inflammation. CONCLUSIONS: Sustained elevation of IL-1ß in the hippocampus may induce cognitive impairment by upregulation of KCC2 during early development.

The Effects of Photobiomodulation Therapy on Porcine Islet Insulin Secretion.

Background and objective: Xenotransplantation of porcine islets to human recipients has been investigated as a potential cure for type 1 diabetes. However, the porcine islets have poor insulin secretion capacity compared with human islets. The objective of this study was to evaluate the effect of photobiomodulation therapy (PBMT) in insulin secretion on isolated porcine islets. Methods: Eight pancreata were harvested from crossbred market porcine and the islets were isolated from the pancreas. The isolated islets were treated with PBMT (wavelength: 633 nm and dosages: 0.0, 15.6, and 31.3 J/cm2) followed by 30-min incubation in low (3.0 mM) or high (16.7 mM) glucose. The relative percentage differences on insulin secretion between three dosages were compared in low and high glucose, respectively. Results: Insulin secretion was higher in samples exposed to 15.6 J/cm2 PBMT in low glucose (p < 0.05), but not in high glucose. When evaluating sex differences, male islets had higher insulin secretion by 15.6 J/cm2 PBMT in low glucose compared with females (p < 0.05). No significant differences were seen in high glucose. When compared within the control groups (0.0 J/cm2 PBMT), the relative changes on insulin secretion in high glucose was significantly higher on male islets (p < 0.05), but not on female islets. Conclusions: PBMT may increase insulin secretion on isolated porcine islets in basal condition, but it may not improve islets' glucose responsiveness to secrete insulin. Male porcine islets may respond to PBMT and glucose stimuli better than female islets on insulin secretion.

Biflavonoids from Ginkgo biloba leaves as a novel anti-atherosclerotic candidate: Inhibition potency and mechanistic analysis.

BACKGROUND: Ginkgo biloba L. is one of the oldest trees on earth, and its leaves have been used since ages as herbal medicine to treat cerebrovascular disorders. It is worth noting that in addition to the widely concerned flavonoids and terpenoids, it also contains various thus far neglected biflavonoids. In fact, biflavonoids are flavonoids consisting of apigenin or its derivatives as monomeric scaffold, and are linked via C-C or C-O-C bond. PURPOSE: Based on the structural similarity of flavonoids, we hypothesized that biflavonoids may play a potential role in the treatment of cerebrovascular diseases. Here, we describe the effectiveness and underlying mechanisms for prevention and treatment of atherosclerosis (AS) by biflavonoids. STUDY DESIGN AND METHODS: Four main biflavonoids in Ginkgo biloba leaves were screened by oleic acid-induced lipid production in HepG2 cells. The non-covalent effects of biflavonoids on the potential targets of atherosclerosis were screened by reverse targeting and molecular dynamics simulation. The interactions between biflavonoids and potential targets were evaluated by an exogenous cell model, which verified the consistency of the simulation results. CONCLUSION: Among all four biflavonoids, ginkgetin significantly inhibited oleic acid-induced lipid production in HepG2 cells and reduced total cholesterol and triglyceride levels. The interaction of ginkgetin with CDK2 through π-alkyl and hydrogen bonds increased the binding of molecules and proteins. Ginkgetin arrested the cells in the G1-S phase, which significantly inhibited abnormal cell growth which closely related to the occurrence and development of atherosclerosis. Biflavonoids could be a promising natural medicine for the treatment of atherosclerosis.

Aucubin as a natural potential anti-acute hepatitis candidate: Inhibitory potency and hepatoprotective mechanism.

BACKGROUND: Hepatic inflammation can substantially impact the development of acute hepatitis. It is a pressing need to identify and exploit novel therapeutic targets as well as effective drug therapies against acute hepatitis. Aucubin (AU) is one of the main active components extracted from the leaves of Eucommia ulmoides and possesses significant anti-inflammatory and antioxidant activities. However, the protective effect and mechanism of AU on acute hepatitis have not been reported yet. PURPOSE: This study aims to investigate the protective effect of AU on LPS-induced acute hepatitis and the mechanism of action. METHODS: The limma package was used to analyze differentially expressed genes (DEGs) between LPS-induced acute hepatitis and normal groups based on Gene Expression Omnibus (GEO) microarray data. Network pharmacology predicted targets for AU therapy against acute hepatitis, and Gene Ontology (GO) enrichment analysis of the biological processes involved in these targets. The key pathways were analyzed by protein-protein interaction, KEGG (Kyoto Encyclopedia of Genes and Genomes), and GSEA (Gene Set Enrichment Analysis) enrichment. The important interaction targets between AU and key pathways were evaluated by molecular simulation. The in silico predicted mechanism was verified based on in vitro and in vivo experiments. RESULTS: A total of 116 intersection targets between AU prediction targets and differentially expressed genes were identified. They were functionally involved in the imbalance of "inflammation-anti-inflammation" and "oxidation-antioxidation" systems in the process of LPS-induced cases. In vitro experiments revealed that AU reduced inflammation in LPS-induced HepG2 cells by reducing the inflammatory cytokines TNF-α, IL-6, as well as iNOS enzyme activity levels. In addition, LPS-induced oxidative stress can be alleviated by AU via adjusting the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Malone dialdehyde (MDA) and reactive oxygen species (ROS). Protein-protein interaction and GSEA results showed that AU might exert anti-inflammatory effects mainly through the STAT3/NF-κB signal pathway. Molecular dynamics simulation as well as in vivo tests further demonstrated AU restrained nuclear transfer of NF-κB (P65), probably through reducing phosphorylation of STAT3. In addition, AU appears to reduce oxidative stress by upregulating NRF2/HO-1. CONCLUSION: We explored potential targets and signal pathways of AU in inhibiting acute hepatitis. AU exerted anti-inflammatory and antioxidant activities and may be a useful candidate drug for the treatment of acute hepatitis.

Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain.

Current pain management is largely limited to opioids and non-steroidal anti-inflammatory drugs. Developing new analgesic drugs remains important to address the unmet medical needs of chronic pain patients. Calcium-activated chloride channel anoctamin-1 (ANO1) is a potential analgesic target. ANO1 is activated by noxious stimuli in peripheral sensory neurons and further induced neural depolarization. Downregulation of ANO1 reduced hyperalgesia and allodynia caused by inflammation and nerve injury. Here we developed a series of 4-arylthiophene-3-carboxylic acid derivatives for proof-of-concept studies of ANO1-targeted analgesia. These efforts led to the identification of the compound DFBTA, 4-(4-chlorophenyl)-2-(2,5-difluorobenzamido)thiophene-3-carboxylic acid, which displays dramatic ANO1 inhibition with IC50 of 24 nM. DFBTA displays very weak cytotoxicity, cardiotoxicity, and acute toxicity (HEK293 proliferation IC50 > 30 µM, hERG IC50 > 30 µM, mouse minimum lethal dosage, MLD>1000 mg/kg), as well as excellent pharmacokinetics properties with oral bioavailability >75% and little brain penetration (<1.5% brain/plasma). Finally, the analgesic efficacy of ANO1 inhibitor was evaluated in animal models. DFBTA shown comparable efficacy to clinical drugs in all inflammatory pain models induced by complete Freund's adjuvant, formalin, and capsaicin. These works provide a useful tool compound and promising results for ANO1-targenting analgesic development.

Seed oil of Rosa roxburghii Tratt against non-alcoholic fatty liver disease in vivo and in vitro through PPARα/PGC-1α-mediated mitochondrial oxidative metabolism.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis and hepatocyte injury, is an obesity-induced metabolic dysregulation with few available therapeutic options. Enhancement of the mitochondrial function was considered as an effective treatment for NALFD. Unsaturated fatty acids (UFAs) have been shown to have beneficial effects on metabolic syndrome disease such as hyperlipidemia, coronary artery disease and cardiovascular diseases. The seed oil of Rosa roxburghii Tratt (ORRT) was of high quality in terms of its high amount of unsaturated fatty acids. However, the effects of ORRT on NALFD have not been reported so far. PURPOSE: The study aimed to evaluate the protective effects and molecular mechanism of ORRT for the treatment of NAFLD in vivo and in vitro. METHODS: The beneficial effects, especially improving the mitochondrial function, and the potential mechanism of ORRT on NAFLD were studied both in vivo and in vitro. Lipid levels were determined by triglyceride (TG), total cholesterol (TC), and Oil Red O staining. Oxidative stress and inflammation were assessed by detecting antioxidant enzyme activity, MDA content, and ELISA assay. Blood TG, TC, HDL-c and LDL-c levels were measured in HFD mice. Western blot analyses were used to determine the levels of the protein involved in fatty acid oxidation, oxidative metabolism, and mitochondria biogenesis and function. The mitochondrial membrane potential level was measured by JC-1 staining to teste the effect of ORRT on mitochondrial function in vitro. GW6471 (inhibitor of PPARα) was used to confirm the relationship between PPARα and PGC-1α. RESULTS: ORRT significantly restrained NAFLD progression by attenuating lipid accumulation, oxidative stress and inflammatory response. Furthermore, ORRT upregulated thermogenesis-related gene expressions, such as uncoupling protein 1 (UCP1) and p38 mitogen-activated protein kinase (p38 MAPK). The results showed that the expression of key genes involved in fatty acid oxidation (e.g., CPT-1α, ACADL, PPARα) and in mitochondrial biogenesis and function (e.g., TFAM, NRF1, PGC-1α, and COX IV) was significantly increased. Together with the observed MMP improvement, these findings suggested that ORRT activated the mitochondrial oxidative pathway. Additionally, GW6471 inhibited the ORRT on promoting the expression of PGC-1α, CPT-1α, and ACADL. In conclusion, ORRT possessed the potential to prevent lipid accumulation via the PPARα/PGC-1α signaling pathway, which could be developed as a natural health-promoting oil against NAFLD.

[Effects of alcohol extract of radish seed on blood lipid, glucose and liver steatosis in ApoE-/- mice].

Objective: To investigate the effects and mechanisms of alcohol extract of Raphani seed (AERS) on blood lipid, blood glucose and hepatic steatosis in ApoE-/- mice. Methods: Sixty ApoE-/- mice were randomly divided into control group (CG), normal saline group (NG), rosiglitazone group (RG) and AERS treatment groups (AERS-L / M / H). Except CG, other groups were fed with high-fat, high-sugar and high-salt diet for 9 weeks. The mice in RG were treated with rosiglitazone (1.33 mg·kg-1, 0.2 ml ·10 g-1) by gavage daily. The mice in CG and NG were treated with equal volume of NS by intragastric administration daily. The mice in AERS groups were treated with AERS at the doses of 100, 300 and 900 mg·kg-1 for 9 weeks, respectively. FPG and Fins were detected. Insulin resistance index (IRI) and liver coefficient (LC) were calculated. The levels of ALT, AST, Leptin (LEP), TNF - α and blood lipid (TC, FFA, etc.) were tested. The expressions of proteins related to liver lipid metabolism (HMG-R、LDL-R、LEP-R) were detected by Western blot. Results: Compared with NG or RG, CG showed significant changes in liver appearance (color, swelling, etc.) and pathology (steatosis, hepatocyte necrosis, etc.), while AERS-M/H groups were similar to CG. Compared with CG, the serum levels of FPG, Fins, IRI, ALT, AST, TNF-α, LC, TG, LDL-C, FFA and LEP were increased significantly (P＜0.05) . Compared with NG, AERS could decrease the above mentioned indicators in a dose-dependent manner (P＜0.05). Compared with RG, the levels of FPG and Fins of AERS-H were increased significantly, while the level of IRI was decreased (P＜0.05). Compared with NG and RG, the protein expressions of HMG-R and LEP-R in AERS groups were decreased, while the protein expression of LDL-R was increased in a dose-dependent manner (P＜0.05). Conclusion: AERS can prevent the increase of blood lipid, glucose and hepatic steatosis induced by high-fat and high-sugar diet in ApoE-/- mice. The mechanism is related to the decrease of FFA and LEP, the inhibition of TNF-α, HMG-R, LEP-R protein expressions and the promotion of LDL-R protein expression.

Therapeutic Efficacy of Sesquiterpene Farnesol in Treatment of Cutibacterium acnes-Induced Dermal Disorders.

Acne vulgaris is a highly prevalent skin disorder requiring treatment and management by dermatologists. Antibiotics such as clindamycin are commonly used to treat acne vulgaris. However, from both medical and public health perspectives, the development of alternative remedies has become essential due to the increase in antibiotic resistance. Topical therapy is useful as a single or combined treatment for mild and moderate acne and is often employed as maintenance therapy. Thus, the current study investigated the anti-inflammatory, antibacterial, and restorative effects of sesquiterpene farnesol on acne vulgaris induced by Cutibacterium acnes (C. acnes) in vitro and in a rat model. The minimum inhibitory concentration (MIC) of farnesol against C. acnes was 0.14 mM, and the IC50 of 24 h exposure to farnesol in HaCaT keratinocytes was approximately 1.4 mM. Moreover, 0.8 mM farnesol exhibited the strongest effects in terms of the alleviation of inflammatory responses and abscesses and necrotic tissue repair in C.acnes-induced acne lesions; 0.4 mM farnesol and clindamycin gel also exerted similar actions after a two-time treatment. By contrast, nearly doubling the tissue repair scores, 0.4 mM farnesol displayed great anti-inflammatory and the strongest reparative actions after a four-time treatment, followed by 0.8 mM farnesol and a commercial gel. Approximately 2-10-fold decreases in interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, found by Western blot analysis, were predominantly consistent with the histopathological findings and tissue repair scores. The basal hydroxypropyl methylcellulose (HPMC) gel did not exert anti-inflammatory or reparative effects on rat acne lesions. Our results suggest that the topical application of a gel containing farnesol is a promising alternative remedy for acne vulgaris.

Effectiveness and safety of acupoint application for chronic obstructive pulmonary disease: A protocol for updated systematic review and meta-analysis.

BACKGROUND: Acute exacerbation is a primary cause of repeated hospitalization and death in chronic obstructive pulmonary disease (COPD) patients. Therefore, how to control the symptoms of COPD at stable stage and reduce the number of acute exacerbation is a hot spot of medical research. Acupoint application (AA) is a significant part of external treatment of traditional Chinese medicine (TCM), Previous researches have reported that AA can be applied to the treatment of COPD. Nevertheless, its effectiveness is still inconclusive. This systematic review (SR) and meta-analysis is designed to appraise its effectiveness and safety for the treatment of patients with COPD. METHODS: Eight databases will be systematically retrieved from their inceptions to February 2021. Inclusion criteria are randomized control trials of AA combined with routine western medicine interventions in the treatment of COPD at stable stage. The primary outcomes we focus on comprise clinical effective rate, TCM symptom score, quality of life, dyspnea, exercise capacity, lung function, frequency of acute exacerbation, adverse events. The research screening, data extraction, and risk of bias assessment will be conducted by 2 individuals independently, and divergence will be adjudicated by a third senior investigator. The Stata 13.1 software will be used for meta-analysis. The confidence of evidence will be classified adopting grading of recommendations assessment, development and evaluation (GRADE) algorithm and methodological quality of this SR will be assessed using assessment of multiple systematic reviews-2 (AMSTAR-2) tool. RESULTS: This SR will provide evidence-based medical proof for the treatment of COPD at stable stage by AA combined with conventional western medicine interventions. The findings of this SR will be presented at relevant conferences and submitted for peer-review publication. CONCLUSIONS: The findings of this SR will provide up-todated summary proof for evaluating the effectiveness and safety of AA for COPD. REGISTRATION NUMBER: INPLASY 202140080.

Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy.

Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied. Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM-dependent store-operated Ca2+ entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin-induced neurotoxicity. Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin.

Advances in Molecular Mechanisms for Traditional Chinese Medicine Actions in Regulating Tumor Immune Responses.

Traditional Chinese medicine (TCM) has been developed for thousands of years with its various biological activities. The interest in TCM in tumor prevention and treatment is rising with its synergistic effect on tumor cells and tumor immunosuppressive microenvironment (TIM). Characteristic of TCM fits well within the whole system and multi-target cancer treatment. Herein we discuss the underlying mechanisms of TCM actions in TIM via regulating immunosuppressive cells, including restoring the antigen presentation function of dendritic cells, enhancing NK cells-mediated killing activity, restraining the functions of myeloid cell-derived suppressor cells, and inhibiting cancer-associated fibroblasts. TCM also regulates tumor progression through enhancing immune response, preventing immune escape and inducing cell death of tumor cells, which triggers immune response in nearby cells. In addition, we discuss TCM in clinical applications and the advantages and disadvantages of TCM in cancer prevention and treatment, as well as current therapeutic challenges and strategies. It might be helpful for understanding the therapeutic potential of TCM for cancer in clinic.

On-demand drug release nanoplatform based on fluorinated aza-BODIPY for imaging-guided chemo-phototherapy.

Intelligent drug delivery systems (DDS), integrating with multi-modal imaging guidance and controlled drug release, have practical significance in enhancing the therapeutic efficiency of tumors. Herein, fluorinated aza-boron-dipyrromethene (NBF) with high near-infrared absorption is synthesized by introducing nonadecafluorodecanoic acid into aza-BODIPY via the amide bond. Through the co-precipitation methods, nanoparticles (NPs) based on NBF are fabricated and the obtained NBF NPs can not only load with DOX with a high loading efficiency (25%, DNBF NPs), but also absorb PFC droplets (1H-perfluoropentane) with bp of 42 °C because of the fluorinated chains inside NBF NPs (PDNBF NPs). Under 808-nm laser irradiation, the hyperthermia effect of NBF could induce the liquid-gas phase transition of PFC droplets, triggering the burst release of DOX and enhancing echo signals for ultrasound imaging as well. With efficient enrichment of PDNBF NPs at tumor site as revealed by in vivo ultrasound imaging and photoacoustic imaging, significant improvement in inhibiting tumor growth is achieved with PDNBF NPs under laser irradiation without noticeable side effects. The work presents a multifunctional organic DDS with great biocompatibility, high drug loading efficiency and light-stimuli-responsive drug release, which provides a new strategy for the manufacture of intelligent composite theranostic nanoplatform.