Oral matrine alleviates CCl4-induced liver fibrosis via preserved HSP72 from modulated gut microbiota.

Hepatic fibrosis is intricately associated with dysregulation of gut microbiota and host metabolomes. Our previous studies have demonstrated that matrine can effectively reduce hepatosteatosis and associated disorders. However, it is poorly understood whether the gut microbiota involved in the attenuation of liver fibrosis by matrine. Herein we explored a novel mechanism of how oral administration of matrine alleviates liver fibrosis by modulating gut microbiota. Administration of matrine not only potently ameliorated liver fibrosis in carbon tetrachloride (CCl4)-induced mice, but also significantly preserved hepatic heat shock protein 72 (HSP72) in vivo and in vitro. Matrine was failed to reduce liver fibrosis when HSP72 upregulation was blocked by the HSP72 antagonist VER-155008. Also, consumption of matrine significantly alleviated gut dysbiosis and fecal metabonomic changes in CCl4-treated mice. Transplanted the faces of matrine-treated mice induced a remarkable upregulation of HSP72 and remission of fibrosis in liver in CCl4-exposed mice and inhibition of TGF-ß1-induced inflammatory response and epithelial-mesenchymal transition (EMT) in AML-12 cells. Furthermore, deficiency of HSP72 partly reversed the intestinal microbial composition that prevented matrine from reducing CCl4-induced liver fibrosis in mice. This study reveals the "gut microbiota-hepatic HSP72" axis as a key mechanism of matrine in reducing liver fibrosis and suggest that this axis may be targeted for developing other new therapies for liver fibrosis.

Water decoction of Pericarpium citri reticulatae and Amomi fructus ameliorates alcohol-induced liver disease involved in the modulation of gut microbiota and TLR4/NF-κB pathway.

Introduction: Alcohol consumption alters the diversity and metabolic activities of gut microbiota, leading to intestinal barrier dysfunction and contributing to the development of alcoholic liver disease (ALD), which is the most prevalent cause of advanced liver diseases. In this study, we investigated the protective effects and action mechanism of an aqueous extraction of Pericarpium citri reticulatae and Amomi fructus (PFE) on alcoholic liver injury. Methods: C57BL/6 mice were used to establish the mouse model of alcoholic liver injury and orally administered 500 and 1,000 mg/kg/d of PFE for 2 weeks. Histopathology, immunohistochemistry, immunofluorescence, Western blotting, qRT-PCR, and 16S rDNA amplicon sequencing were used to analyze the mechanism of action of PFE in the treatment of alcohol-induced liver injury. Results: Treatment with PFE significantly improved alcohol-induced liver injury, as illustrated by the normalization of serum alanine aminotransferase, aspartate aminotransferase, total triglyceride, and cholesterol levels in ALD mice in a dose-dependent manner. Administration of PFE not only maintained the intestinal barrier integrity prominently by upregulating mucous production and tight junction protein expressions but also sensibly reversed the dysregulation of intestinal microecology in alcohol-treated mice. Furthermore, PFE treatment significantly reduced hepatic lipopolysaccharide (LPS) and attenuated oxidative stress as well as inflammation related to the TLR4/NF-κB signaling pathway. The PFE supplementation also significantly promoted the production of short-chain fatty acids (SCFAs) in the ALD mice. Conclusion: Administration of PFE effectively prevents alcohol-induced liver injury and may also regulate the LPS-involved gut-liver axis; this could provide valuable insights for the development of drugs to prevent and treat ALD.

Parabacteroides goldsteinii enriched by Pericarpium Citri Reticulatae 'Chachiensis' polysaccharides improves colitis via the inhibition of lipopolysaccharide-involved PI3K-Akt signaling pathway.

Epidemiological and preclinical studies have indicated a factual association between gut microbiota dysbiosis and high incidence of colitis. Dietary polysaccharides can specifically shift the composition of gut microbiome response to colitis. Here we validated the preventive role of polysaccharides from Pericarpium Citri Reticulatae 'Chachiensis' (PCRCP), a well-known traditional Chinese medicine, in colitis induced by dextrose sodium sulfate (DSS) in both rats and mice. We found that treatment with PCRCP not only significantly reduced DSS-induced colitis via down-regulating colonic inflammatory signaling pathways including PI3K-Akt, NLRs and NF-κB, but also enhanced colonic barrier integrity in rats. These protective activities of PCRCP against DSS-induced injuries in rats were in part due to the modulation of the gut microbiota revealed by both broad-spectrum antibiotic (ABX)-deleted bacterial and non-oral treatments. Furthermore, the improvement of PCRCP on colitis was impaired by intestinal neomycin-sensitive bacteria in DSS-exposed mice. Specifically, in vivo and in vitro treatment with PCRCP led to a highly sensible enrichment in the gut commensal Parabacteroides goldsteinii. Administration of Parabacteroides goldsteinii significantly alleviated typical symptoms of colitis and suppressed the activation of PI3K-Akt-involved inflammatory response in DSS-exposed mice. The anti-colitic effects of Parabacteroides goldsteinii were abolished after the activation of PI3K-Akt signaling pathway by lipopolysaccharide treatment in mice exposed to DSS. This study provides new insights into an anti-colitic mechanism driven by PCRCP and highlights the potential prebiotic of Parabacteroides goldsteinii for the prevention of ulcerative colitis.

Four new sesquiterpenoids from the aerial parts of Pogostemon cablin (Blanco.) Benth. and their hypoglycemic activity.

Four previously undescribed sesquiterpenoids (1-4), including two natural guaiane-type sesquiterpenoids (1-2), a rearranged guaiane-type sesquiterpenoid (3), and a norsesquiterpenoid (4), were isolated from the ethanol extract of the aerial parts of Pogostemon cablin (Blanco.) Benth. Their chemical structures were determined based on extensive spectroscopic data analysis, including UV, IR, NMR, HRESIMS, and CD spectroscopy. Compound 1 exhibited a good hypoglycemic activity with glucose uptake of 124.3% and 131.2% in myotubes, respectively, at the concentrations of 20 and 40 µM and showed no cytotoxicity. These findings provide a material basis for further research on P. cablin.

Chemical Composition of Essential Oil from Citrus reticulata Blanco cv. Chachiensis (Chachi) and Its Anti-Mosquito Activity against Pyrethroid-Resistant Aedes albopictus.

The overuse of synthetic insecticides has led to various negative consequences, including insecticide resistance, environmental pollution, and harm to public health. This may be ameliorated by using insecticides derived from botanical sources. The primary objective of this study was to evaluate the anti-mosquito activity of the essential oil (EO) of Citrus reticulata Blanco cv. Chachiensis (Chachi) (referred to as CRB) at immature, semi-mature, and mature stages. The chemical compositions of the CRB EO were analyzed using GC-MS. The main components were identified to be D-limonene and γ-terpinene. The contents of D-limonene at the immature, semi-mature, and mature stages were 62.35%, 76.72%, and 73.15%, respectively; the corresponding contents of γ-terpinene were 14.26%, 11.04%, and 11.27%, respectively. In addition, the corresponding contents of a characteristic component, methyl 2-aminobenzoate, were 4.95%, 1.93%, and 2.15%, respectively. CRB EO exhibited significant larvicidal activity against Aedes albopictus (Ae. albopictus, Diptera: Culicidae), with the 50% lethal doses being 65.32, 61.47, and 65.91 mg/L for immature, semi-mature, and mature CRB EO, respectively. CRB EO was able to inhibit acetylcholinesterase and three detoxification enzymes, significantly reduce the diversity of internal microbiota in mosquitoes, and decrease the relative abundance of core species within the microbiota. The present results may provide novel insights into the utilization of plant-derived essential oils in anti-mosquitoes.

N-p-coumaroyloctopamine ameliorates hepatic glucose metabolism and oxidative stress involved in a PI3K/AKT/GSK3ß pathway.

Type 2 diabetes mellitus is regarded as a chronic metabolic disease characterized by hyperglycemia. Long-term hyperglycemia may result in oxidative stress, damage pancreatic ß-cell function and induce insulin resistance. Herein we explored the anti-hypoglycemic effects and mechanisms of action of N-p-coumaroyloctopamine (N-p-CO) in vitro and in vivo. N-p-CO exhibited high antioxidant activity, as indicated by the increased activity of SOD, GSH and GSH-Px in HL-7702 cells induced by both high glucose (HG) and palmitic acid (PA). N-p-CO treatment significantly augmented glucose uptake and glycogen synthesis in HG/PA-treated HL-7702 cells. Moreover, administration of N-p-CO in diabetic mice induced by both high-fat diet (HFD) and streptozotocin (STZ) not only significantly increased the antioxidant levels of GSH-PX, SOD and GSH, but also dramatically alleviated hyperglycemia and hepatic glucose metabolism in a dose-dependent manner. More importantly, N-p-CO upregulated the expressions of PI3K, AKT and GSK3ß proteins in both HG/PA-induced HL-7702 cells and HFD/STZ-induced mice. These findings clearly suggest that N-p-CO exerts anti-hypoglycemic and anti-oxidant effects, most probably via the regulation of a PI3K/AKT/GSK3ß signaling pathway. Thus, N-p-CO may have high potentials as a new candidate for the prevention and treatment of diabetes.

Thiazolidine-2,4-dione derivatives as potential α-glucosidase inhibitors: Synthesis, inhibitory activity, binding interaction and hypoglycemic activity.

In order to find effective α-glucosidase inhibitors, a series of thiazolidine-2,4-dione derivatives (C1 âˆ¼ 36) were synthesized and evaluated for α-glucosidase inhibitory activity. Compared to positive control acarbose (IC50 = 654.35 ± 65.81 µM), all compounds (C1 âˆ¼ 36) showed stronger α-glucosidase inhibitory activity with IC50 values of 0.52 ± 0.06 âˆ¼ 9.31 ± 0.96 µM. Among them, C23 with the best anti-α-glucosidase activity was a reversible mixed-type inhibitor. Fluorescence quenching suggested the binding process of C23 with α-glucosidase in a static process. Fluorescence quenching, CD spectra, and 3D fluorescence spectra results also implied that the binding of C23 with α-glucosidase caused the conformational change of α-glucosidase to inhibit the activity. Molecular docking displayed the binding interaction of C23 with α-glucosidase. Compound C23 (8 âˆ¼ 64 µM) showed no cytotoxicity against LO2 and 293 cells. Moreover, oral administration of C23 (50 mg/kg) could reduce blood glucose and improve glucose tolerance in mice.

Isolation, structure modification, and anti-rheumatoid arthritis activity of isopimarane-type diterpenoids from Orthosiphon aristatus.

Orthosiphon aristatus is a well-known folkloric medicine and herb for Guangdong soup for the treatment of rheumatism in China. Eight isopimarane-type and migrated pimarane-type diterpenoids (1-8), including a new one with a rarely occurring α,ß-unsaturated diketone C-ring, were isolated from O. aristatus. Their structures were determined by spectroscopic methods and quantum chemical calculations. Furthermore, the most abundant compound, orthosiphol K, was structurally modified by modern synthetic techniques to give seven new derivatives (9-15). The anti-rheumatoid arthritis activity of these diterpenoids were evaluated on a TNF-α induced MH7A human rheumatoid fibroblast-like synoviocyte model. Compound 10 showed the most potent activity among these compounds. Based on their inhibitory effects on the release levels of IL-1ß, the preliminary structure-activity relationships were concluded. Furthermore, western blot analysis revealed that 10 could increase the expression of IκBα and decrease the expression of NF-κB p65, and the expression levels of COX-2 and NLRP3 proteins were consequently down-regulated.

Lignan glucosides from Gentiana macrophylla with potential anti-arthritis and hepatoprotective activities.

Ten lignans, including six previously undescribed phenolic ester glycosyl lignans (1-6), were isolated from a well-known traditional Chinese medicine, Qin-Jiao, which is the dry root of Gentiana macrophylla Pall. (Gentianaceae). Their structures were determined by spectroscopic and chemical methods, especially 2D NMR techniques. Quantum chemical calculations of theoretical ECD spectra allowed the determination of their absolute configurations. Refer to its traditional applications for the treatment of rheumatic arthralgia and hepatopathy, these compounds were evaluated on a TNF-α induced MH7A human synoviocyte inflammation model and a D-GalN induced AML12 hepatocyte injury model. Compounds 1, 2, 5, and 6 significantly reduced the release of proinflammatory cytokine IL-1ß in MH7A cells at 15 µM and they also could strongly protect AML12 cells against D-GalN injury at 30 µM. Flow cytometry and Western blot analysis showed that compound 5 ameliorated D-GalN induced AML12 cell apoptosis by upregulating the expression of anti-apoptotic Bcl-2 protein and down-regulating the expression of pro-apoptotic Bax protein.

Inhibitory effect of liriopesides B in combination with gemcitabine on human pancreatic cancer cells.

Gemcitabine (GEM) is a standard chemotherapeutic agent for patients with pancreatic cancer; however, GEM-based chemotherapy has a high rate of toxicity. A combination of GEM and active constituents from natural products may enhance its therapeutic efficacy and reduce its toxicity. This study investigated the synergistic effects of the combination of liriopesides B (LirB) from Liriope spicata var. prolifera and GEM on human pancreatic cancer cells. The results of our study showed that the combination of LirB and GEM synergistically decreased the viability of pancreatic cancer cells. The combination also caused a strong increase in apoptosis and a strong decrease in cell migration and invasion. Furthermore, LirB combined with GEM had potent inhibitory effects on pancreatic cancer stem cells (CSCs). Studies on the mechanisms of action showed that the combination more potently inhibited protein kinase B (Akt) and nuclear factor kappa B (NF-κB), as well as the downstream antiapoptotic molecules B-cell lymphoma 2 (Bcl-2) and survivin than either agent used alone. The results of this study suggest that the combination of LirB with GEM may improve the efficacy of GEM for the treatment of pancreatic cancer.

Hepatoprotective effects of Niudali (Callerya speciosa) root aqueous extracts against tetrachloromethane-induced acute liver injury and inflammation.

Niudali (Callerya speciosa) is commonly grown in southeastern regions of China and consumed as a food ingredient. Although Niudali root extracts showed various biological activities, the hepatoprotective effects of Niudali root phytochemicals are not fully studied. Herein, we prepared two Niudali root aqueous extracts, namely, c and Niudali polysaccharides-enriched extract (NPE), and identified an alkaloid, (hypaphorine) in NEW. The hepatoprotective effects of NWE, NPE, and hypaphorine were evaluated in an acute liver injury model induced by carbon tetrachloride (CCl4) in mice. Pathohistological examination and blood chemistry assays showed that treatment of NWE, NPE, and hypaphorine alleviated CCl4-induced liver damage by lowering the liver injury score (by 75.51%, 80.01%, and 41.22%) and serum aspartate and alanine transaminases level (by 63.24%, 85.22%, and 49.74% and by 78.73%, 80.08%, and 81.70%), respectively. NWE, NPE, and hypaphorine also reduced CCl4-induced hepatic oxidative stresses in the liver tissue by decreasing the levels of malondialdehyde (by 40.00%, 51.25%, and 28.75%) and reactive oxygen species (by 30.22%, 36.14%, and 33.54%) while increasing the levels of antioxidant enzymes including superoxide dismutase (by 21.36%, 21.64%, and 8.90%), catalase (by 22.13%, 33.33%, and 5.39%), and glutathione (by 84.87%, 90.65%, and 80.53%), respectively. Mechanistic assays showed that NWE, NPE, and hypaphorine alleviated liver damage by mediating inflammatory biomarkers (e.g., pro-inflammatory cytokines) via the signaling pathways of mitogen-activated protein kinases and nuclear factor-κB. Findings from our study extend the understanding of Niudali's hepatoprotective effects, which is useful for its development as a dietary intervention for liver inflammation.

Hirsutinolide-type sesquiterpenoids with anti-prostate cancer activity from Cyanthillium cinereum.

Four previously undescribed hirsutinolide-type sesquiterpenoids, cyanolides A-D (1-4), along with twelve known analogues (5-16), were isolated from the aerial parts of Cyanthillium cinereum. Their structures were determined by comprehensive analysis of NMR, HRESIMS, and ECD spectra. Compound 1 is a rarely occurring hirsutinolide-type sesquiterpenoid with 1,4-ether ring ruptured and containing a chlorine atom, and compounds 13-16 were reported from this plant for the first time. All compounds were tested for their inhibiting effects on prostate cancer cells. As a result, compounds 1, 3, and 8-14 exhibited significant anti-prostate cancer activity against PC-3 and LNCaP cells with IC50 values ranging from 2.2 ± 0.4 to 8.5 ± 0.7 µM and 3.0 ± 0.7 to 10.5 ± 1.1 µM, respectively. The preliminary structure-activity relationship was discussed. Further investigation showed that compound 1 induced apoptosis in PC-3 cells.

Terpenoid Glucosides from Gentiana macrophylla That Attenuate TNF-α Induced Pulmonary Inflammation in A549 Cells.

Four previously undescribed terpenoid glucosides, including one sesquiterpenoid di-glucoside (1), two new iridoid glucosides (2, 3), and a new triterpenoid tri-glucoside (4), were isolated from a 70% ethanol extract of the root of Gentiana macrophylla (Gentianaceae), along with eight known terpenoids. Their structures were determined by spectroscopic techniques, including 1D, 2D NMR, and HRMS (ESI), as well as chemical methods. The absolute configuration of compound 1 was determined by quantum chemical calculation of its theoretical electronic circular dichroism (ECD) spectrum. The sugar moieties of all the new compounds were confirmed to be D-glucose by GC analysis after acid hydrolysis and acetylation. Anti-pulmonary inflammation activity of the iridoids were evaluated on a TNF-α induced inflammation model in A549 cells. Compound 2 could significantly alleviate the release of proinflammatory cytokines IL-1ß and IL-8 and increase the expression of anti-inflammatory cytokine IL-10.

Naproxen-Derived New Compound Inhibits the NF-κB, MAPK and PI3K/Akt Signaling Pathways Synergistically with Resveratrol in RAW264.7 Cells.

Naproxen is widely used for anti-inflammatory treatment but it can lead to serious side effects. To improve the anti-inflammatory activity and safety, a novel naproxen derivative containing cinnamic acid (NDC) was synthesized and used in combination with resveratrol. The results showed that the combination of NDC and resveratrol at different ratios have a synergistic anti-inflammatory efficacy in RAW264.7 macrophage cells. It was indicated that the combination of NDC and resveratrol at a ratio of 2:1 significantly inhibited the expression of carbon monoxide (NO), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), induced nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and reactive oxygen species (ROS) without detectable side effects on cell viability. Further studies revealed that these anti-inflammatory effects were mediated by the activation of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling pathways, respectively. Taken together, these results highlighted the synergistic NDC and resveratrol anti-inflammatory activity that could be further explored as a strategy for the treatment of inflammatory disease with an improved safety profile.

Ultrasonic assisted extraction, characterization and gut microbiota-dependent anti-obesity effect of polysaccharide from Pericarpium Citri Reticulatae 'Chachiensis'.

Pericarpium Citri Reticulatae 'Chachiensis' (PCRC), the premium aged pericarps of Pericarpium Citri Reticulatae, is widely used in traditional Chinese medicines with a diversity of promising bioactivity. Herein we report the extraction, characterization and underlying mechanism of anti-metabolic syndrome of an arabinan-rich polysaccharide from PCRC (PCRCP). This polysaccharide was obtained in a 7.0% yield by using ultrasound-assisted extraction under the optimized conditions of 30 mL/g liquid-to-solid ratio, 250 W ultrasound power for 20 min at 90 °C with pH 4.5. The PCRCP with an average molecular weight of 122.0 kDa, is mainly composed of D-galacturonic acid, arabinose and galactose, which may link via 1,4-linked Gal(p)-UA, 1,4-linked Ara(f) and 1,4-linked Gal(p). Supplementation with PCRCP not only effectively alleviated the weight gain, adiposity and hyperglycemia, but also regulated the key metabolic pathways involved in the de novo synthesis and ß-oxidation of fatty acid in high-fat diet (HFD)-fed mice. Furthermore, PCRCP treatment caused a significant normalization in the intestinal barrier and composition of gut microbiota in mice fed by HFD. Notably, PCRCP selectively enriched Lactobacillus johnsonii at the family-genus-species levels, a known commensal bacterium, the level of which was decreased in mice fed by HFD. The depletion of microbiome induced by antibiotics, significantly compromised the effects of anti-metabolic syndrome of PCRCP in mice fed by HFD, demonstrating that the protective phenotype of PCRCP against anti-obesity is dependent on gut microbiota. PCRCP is exploitable as a potential prebiotic for the intervention of obesity and its complications.

Oleuropein-Rich Jasminum Grandiflorum Flower Extract Regulates the LKB1-PGC-1α Axis Related to the Attenuation of Hepatocellular Lipid Dysmetabolism.

Diets() rich in fat are a major() cause() of metabolic disease(), and nutritional() food has been widely() used() to counteract the metabolic disorders such() as obesity() and fatty() liver(). The present study investigated the effects of oleuropein-enriched extract() from Jasminum grandiflorum L. flowers (OLE-JGF) in high-fat diet() (HFD)-fed mice and oleic acid() (OA)-treated AML-12 cells. Treatment() of HFD-fed mice with 0.6% OLE-JGF for 8 weeks significantly reduced body and liver() weights, as well as attenuating lipid dysmetabolism and hepatic steatosis. OLE-JGF administration() prominently suppressed the mRNA expressions() of monocyte chemoattractant protein()-1 (MCP-1) and cluster of differentiation 68 (CD68), and it also downregulated acetyl-CoA carboxylase (ACC) and fatty() acid() synthase (FAS) as well as sterol-regulatory-element()-binding protein() (SREBP-1c) in the liver(). Meanwhile, mitochondrial DNA and uncoupling protein() 2 (UCP2) were upregulated along with the increased expression() of mitochondrial biogenic promoters including liver() kinase B1 (LKB1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear() factor()-erythroid-derived 2-like 2 (Nrf2), and mitochondrial transcription factor() A (Tfam), but did not change AMP-activated protein() kinase (AMPK) in liver(). The lipid droplets were decreased significantly after treatment() with 80 µM oleuropein for 24 h in OA-induced AML-12 cells. Furthermore, oleuropein significantly inhibited ACC mRNA expression() and upregulated LKB1, PGC-1α, and Tfam mRNA levels, as well as increasing the binding level of LKB1 to PGC-1α promoter in OA-induced cells. These findings indicate() that OLE-JGF reduces hepatic lipid deposition in HFD-fed mice, as well as the fact that OA-induced liver() cells may be partly() attributed to upregulation of the LKB1-PGC-1α axis, which mediates hepatic lipogenesis and mitochondrial biogenesis. Our study provides a scientific() basis() for the benefits and potential() use() of the J. grandiflorum flower as a food supplement() for the prevention() and treatment() of metabolic disease().

Complanatuside alleviates inflammatory cell damage induced by pro-inflammatory cytokines in skin keratinocytes.

Cytokine-mediated inflammatory response is considered a cause of skin lesion in COVID-19 patients. Complanatuside is a flavonol glycoside isolated from Astragalus complanatus. Flavonoids from Astragalus complanatus were reported to have anti-inflammatory and anticancer activities but the potential protective effect of complanatuside on cytokine-induced inflammatory damage in skin keratinocytes is not known. The aim of this study is to explore the inhibitory effect of complanatuside on inflammation and its underlying mechanisms in skin epithelial HaCaT cells treated with inflammatory cytokines. The combination of IFN-γ, TNF-α, and IL-6 decreased cell viability, increased cell death, and pyroptosis in HaCaT cells. Treatment with complanatuside alleviated the effects of the cytokine combination on HaCaT cells. Complanatuside down-regulated pyroptosis related to NLRP3, GSDMD, and ASC. The effects of complanatuside were related to vast reductions in the levels of iNOS, COX-2, and ROS. Results of the present study indicate that complanatuside inhibited inflammation and protected the cells from inflammatory cell damage in HaCaT cells treated with the combination of IFN-γ, TNF-α, and IL-6. Complanatuside may be a promising candidate for inhibiting COVID-19 related skin inflammatory damage.

Six pairs of phenylpropanoid enantiomers from Cinnamomum mollifolium.

Six pairs of undescribed phenylglycerol benzoate enantiomers, (±)-mollifolines A-F, which can also be categorized into three two-pairs of epimers, were isolated from Cinnamomum mollifolium H. W. Li (Lauraceae). The relative configurations (threo or erythro) of the epimers were determined by conformational searching of the lowest energy conformers and analyses of the relationship between the dihedral angle of H-7'─C-7'─C-8'─H-8' and the 3JH-7', H-8' coupling constant according to the Karplus equation. Furthermore, intramolecular hydrogen bonds were proved to play an important role in stabilizing the lowest conformations by using reduced density gradient (RDG) method for noncovalent interactions. Chiral resolutions of these enantiomer pairs were accomplished by immobilized polysaccharide derivative-based chiral HPLC columns. Absolute configurations of the 12 optically pure isomers were finally determined by quantum chemical time-dependent density functional theory (TDDFT) calculations of their electronic circular dichroism (ECD) spectra.

Polysaccharides from Callerya speciosa alleviate metabolic disorders and gut microbiota dysbiosis in diet-induced obese C57BL/6 mice.

Callerya speciosa ("Niu Dali" in Chinese) is a well-known edible plant in Southeast China. C. speciosa roots contain a high level of polysaccharides, which have been reported to show multiple health-promoting effects. In the current study, the anti-obesity effects of a crude extract of C. speciosa polysaccharides (NP) and its underlying mechanisms of action are investigated. C57BL/6 mice were divided into three groups and fed either a standard diet or a high-fat diet (HFD). The HFD + NP group mice received oral administration of NP (100 mg per kg per day) every other day for 10 weeks. NP supplementation alleviated HFD-induced diabetic biomarkers including body weight gain, hyperlipidemia, liver steatosis, and adipocyte hypertrophy. Western blot and RT-PCR analyses revealed that NP inhibited hepatic de novo lipogenesis and adipogenesis (i.e. decreased expression of Srebp1c, Fas, Cebpα, and Pparγ), stimulated adipocyte lipolysis (enhanced mRNA expression of Hsl and Mgl), and attenuated HFD-induced hepatic inflammation (decreased expression of TNF-α and NF-κB p65). Furthermore, 16S rDNA and GC-MS analyses showed that NP supplementation restored the Firmicutes/Bacteroidetes proportion, elevated colon-derived SCFAs, especially acetic acid content, and increased the relative abundance of genera associated with SCFA production in HFD-fed mice. Findings from this study suggest that NP alleviated HFD-induced obesity in a mouse model, which was possibly due to its ameliorative effects on diet-induced gut dysbiosis. Polysaccharides from C. speciosa are promising prebiotics and they may be further developed as functional foods for the management of obesity.

Novel 18ß-glycyrrhetinic acid derivatives as a Two-in-One agent with potent antimicrobial and anti-inflammatory activity.

18ß-glycyrrhetinic acid (GA) is a well-known natural compound of oleanane-type triterpene and is found possessing antimicrobial and anti-inflammatory properties. Nonetheless, its relatively low bioactivity restricts its potential in pharmaceutical applications. To maximize the potential use of this natural herbal compound as antimicrobial and anti-inflammatory agents, the rational modification of GA to enhance its pharmacological activity with low toxicity and to understand the mechanism of action is critically essential. We reported herein the design and synthesis of a series of new GA derivatives. The antimicrobial activities of these new compounds were evaluated by inhibition zone test and minimum inhibitory concentration (MIC) assay. In addition, the anti-inflammatory activity was evaluated by LPS induced BV2 cells inflammation model and 12-O-tetradecanoyl phorbol-13-acetate (TPA) induced ear inflammation mice model. It was found that the derivatives functionalized with a di-substituted phenyl group at the 2-position of GA generally displayed high antimicrobial activity against Gram-positive bacteria (MIC down to 2.5 µM) and potent anti-inflammatory effects (inhibition of NO production up to 55%, comparable to dexamethasone). The in vitro and in vivo results also showed that GA-O-02 and GA-O-06 exert their anti-inflammatory activities through downregulation of NO, pro-inflammatory cytokines and chemokines (IL-1ß, IL-6, IL-12, TNF-α, MCP-1 and MIP-1α) and upregulation of anti-inflammatory cytokines (IL-10). The anti-inflammatory mechanism may involve the inhibition of NF-κB, MAPKs and PI3K/Akt related inflammatory signaling pathways and activation of Nrf2/HO-1 signaling pathway. The results demonstrated that GA-O-02 and GA-O-06 possess great application potential as potent antimicrobial and anti-inflammatory agents.