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1.
Bioact Mater ; 20: 194-207, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35702607

RESUMO

Meniscus is a wedge-shaped fibrocartilaginous tissue, playing important roles in maintaining joint stability and function. Meniscus injuries are difficult to heal and frequently progress into structural breakdown, which then leads to osteoarthritis. Regeneration of heterogeneous tissue engineering meniscus (TEM) continues to be a scientific and translational challenge. The morphology, tissue architecture, mechanical strength, and functional applications of the cultivated TEMs have not been able to meet clinical needs, which may due to the negligent attention on the importance of microenvironment in vitro and in vivo. Herein, we combined the 3D (three-dimensional)-printed gradient porous scaffolds, spatiotemporal partition release of growth factors, and anti-inflammatory and anti-oxidant microenvironment regulation of Ac2-26 peptide to prepare a versatile meniscus composite scaffold with heterogeneous bionic structures, excellent biomechanical properties and anti-inflammatory and anti-oxidant effects. By observing the results of cell activity and differentiation, and biomechanics under anti-inflammatory and anti-oxidant microenvironments in vitro, we explored the effects of anti-inflammatory and anti-oxidant microenvironments on construction of regional and functional heterogeneous TEM via the growth process regulation, with a view to cultivating a high-quality of TEM from bench to bedside.

2.
Int J Pharm ; 623: 121884, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35661797

RESUMO

Co-delivery of anti-inflammatory drugs and reactive oxygen species (ROS) scavengers by stimuli-responsive oral nanoparticles is deemed to be a favorable strategy for inflammatory bowel disease (IBD) therapy. In this study, using micelles formed by CUR conjugated hydroxyethyl starch (HES) as vehicles, dexamethasone (DEX)-loaded HES-CUR nanoparticles (DHC NPs) with desirable size, negative surface charge, good stability in the harsh gastric environment, and excellent ROS scavenging activity are developed as a colon-targeted oral formulation for treating IBD. Due to the degradation of HES in response to α-amylase overexpressed in the inflamed colon, the DHC NPs release drugs in an α-amylase-responsive manner. Meanwhile, the DHC NPs can be effectively internalized by macrophages and show excellent cytocompatibility with macrophages since they are composed of food-derived compounds. Importantly, in vivo studies reveal that the DHC NPs are capable of targeting the inflamed colon induced by dextran sulfate sodium (DSS), and the targeted and combination therapy enhances the efficacy of free DEX and significantly relieves the impairment caused by DSS-induced ulcerative colitis. Incorporating the merits of targeted drug delivery and combined therapy with an anti-inflammatory drug and ROS scavenger, the DHC NPs are promising for developing novel oral formulations for IBD therapy.

3.
Bioorg Med Chem ; 68: 116857, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35661849

RESUMO

Africane-type sesquiterpenoids are a unique tricyclic carbon architecture sesquiterpenoid isolated as natural products. Δ9(15) -africanene has been reported to exhibit anti-inflammatory activity for carrageenan-induced rat foot edema. In this study, we reported structure-activity relationship study of africane-type sesquiterpenoids and found that some africane-type sesquiterpenoid analogs and their synthetic intermediate showed potent anti-inflammatory activity. To identify the mode of action of africane-type sesquiterpenoids and their synthetic intermediate, we evaluated the anti-inflammatory activity using lipopolysaccharide (LPS)-stimulated mouse macrophage RAW264.7 cells. Treatment with the africane-type compounds and their synthetic intermediate suppressed LPS-induced expressions of Cox-2 protein and mRNAs of the inflammatory cytokines IL-1ß and IL-6 at the concentrations that did not affect cell viability. Interestingly, although these africane-type compounds and their synthetic intermediate suppressed the pro-inflammatory cytokines' expressions, the compounds did not modulate NF-κB activation. These results suggest that the africane-type compounds and their synthetic intermediate are anti-inflammatory compounds that suppress the expression of LPS-induced inflammatory mediators independently of NF-κB activation.


Assuntos
Lipopolissacarídeos , Sesquiterpenos , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Sesquiterpenos/farmacologia
5.
Phytochemistry ; 201: 113260, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35667577

RESUMO

Eight C6-C3-based bibenzyl derivatives (dengraphenols A-G, K), three mono-bibenzyls (dengraphenols I, L-M), one bis-bibenzyl (dengraphenol H), one oxyneolignane (dengraphenol J), one phenanthrene (dengraphenol N), and one picrotoxane-type sesquiterpene (dengrasusane A) were isolated from the stems of Dendrobium gratiosissimum. The resolution of dengraphenols A-J by chiral HPLC afforded ten pairs of enantiomers [(±)-dengraphenols A-J]. Their structures with absolute configurations were elucidated on the basis of comprehensive spectroscopic analyses, computational calculation methods and single-crystal X-ray diffraction, among which twenty-four [(±)-dengraphenols A-E, (+)-dengraphenol F, (±)-dengraphenols G-J, dengraphenols K-N, dengrasusane A] were undescribed. Ten compounds [(±)-dengraphenol B, (±)-dengraphenols D-E, (±)-dengraphenol H, (-)-dengraphenol I and dengraphenol N)] showed potent cytotoxicity against eight human cancer cell lines (A431, A2780, H460, HCT8, BGC823, SW1990, Daoy, and HGC27) with IC50 values of 3.77-9.75 µM. At a concentration of 10 µM, (-)-dengraphenol C, (±)-dengraphenol F, and (±)-dengraphenol K exhibited remarkable hepatoprotective activity against APAP-induced toxicity with a cell survival rate of 65.8%, 70.6% and 73.5%, respectively; dengraphenol N displayed significant anti-inflammatory effects; and dengraphenol K showed strong inhibitory activity against α-glucosidase with IC50 values of 5.71 µM. These results would provide potential compounds for drug discovery.

6.
Bioorg Chem ; 127: 105939, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35700569

RESUMO

Thirty-three novel paeonol etherized aryl urea derivatives (PEUs) were synthesized via a bromination-Williamson Ether Synthesis-deprotection-nucleophilic addition reaction sequence. The structures of PEUs were characterized by LC-MS, HRMS, 1H NMR and 13C NMR spectra. The levels of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages were initially employed to evaluate the anti-inflammatory effects of all compounds. Remarkably, b16 exhibited a good anti-inflammatory activity at 2.5 µm which is the same as the potency of paeonol at 20 µm. The results of mechanism research displayed that the anti-inflammatory effect of b16 was ascribed to the inhibition of the TLR4/MyD88 signaling pathway and inflammatory factors. Additionally, b16 distinctly reduced the generation of free radicals in macrophages and strikingly increased the mitochondrial membrane potential. According to the structure-activity relationships (SAR) of PEUs, the incorporation of halogens on the benzene ring and the hydrogen of phenol hydroxyl substituted by aryl urea, were beneficial to enhance the anti-inflammatory activities. Molecular docking results illustrated that the binding ability of b16 to TLR4 was stronger than that of paeonol. In summary, the novel aryl urea-derivied paeonol b16 could be a new promising candidate for the treatment of inflammation-related diseases.

7.
Biomed Pharmacother ; 153: 113295, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35724507

RESUMO

Kaempferol 3-O-(2G-glucosylrutinoside)-7-O-glucoside (KGG) has isolated from Hosta plantaginea flowers and possessed an inhibitory effect on cyclooxygenase 2 (COX-2), could be effective in inhibiting inflammation. However, the anti-inflammatory activity and mechanism of KGG remain unknown. In this study, for the first time, the anti-inflammatory effect of KGG and its potential molecular mechanisms were explored in cells. KGG had no cytotoxicity at concentrations of 1.25, 2.5, 5, 10, 20, and 40 µM by Cell Counting kit-8 assay in RAW 264.7 cells. Besides, KGG concentration-dependently (1.25, 2.5, and 5 µM) inhibited secretions of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6 in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Western blot showed that the phosphorylation of nuclear factor kappa-B (NF-κB) p65, inhibitor of NF-κB (IκB), p38 MAPK, c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (Erk), and protein kinase B (Akt), together with inducible nitric oxide synthase (iNOS) and COX-2 were significantly attenuated by KGG (1.25, 2.5, and 5 µM) in a concentration-dependent relationship. Meanwhile, KGG remarkably enhanced the protein expression of IκB. Taken together, KGG may be one of bioactive phytochemicals from H. plantaginea flowers, and be an anti-inflammatory agent via inhibiting NF-κB, mitogen-activated protein kinases (MAPKs), and Akt signaling pathways.

8.
J Ethnopharmacol ; 296: 115492, 2022 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-35724746

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Bocconia arborea S. Watson (Papaveraceae) is known as "palo llora sangre" and is used in Mexican traditional medicine for the treatment of infections, it is also used as anxiolytic, analgesic, and antidiabetic, among others. AIM OF THE STUDY: to evaluate the antinociceptive and gastroprotective activities of extracts from B. arborea and dihydrosanguinarine (DHS) in murine models. MATERIALS AND METHODS: Organic extracts [hexane (HEX), dichloromethane (DCM) and methanol (MeOH)] were obtained by maceration. DHS was isolated and purified from HEX and DCM by precipitation and chromatographic column, respectively. Organic extracts and DHS were evaluated to determine their antinociceptive effect using formalin test in murine model. Also, the ambulatory effect of the HEX and DHS was determined in Open field test. The possible mechanism of action of DHS was explored in the presence of naltrexone (NTX, 1 mg/kg, i.p.), and picrotoxin (PTX, 1 mg/kg, i.p.). Gastric damage as possible adverse effect or gastroprotection were also investigated. Whereas DHS acute toxicological study was done, and 100 mg/kg of DHS was examined by electroencephalographic (EEG) analysis to discard neurotoxic effects. RESULTS: The B. arborea extracts significantly showed effects in both neurogenic and inflammatory phases of the formalin test, where the HEX extract reached the major antinociceptive effect. A significant and dose-response (10, 30, and 100 mg/kg) antinociceptive activity was observed with the HEX (ED50 = 69 mg/kg) and DHS (ED50 = 85 mg/kg) resembling the effect of the reference analgesic drug tramadol (30 mg/kg). The significant effect of DHS was inhibited in the presence of NTX and PTX. Neither the extracts or DHS produced sedative effects or gastric damage per se at antinociceptive doses. The EEG analysis demonstrated central depressant activity but not sedative or neurotoxic effects at the highest antinociceptive dosage tested, and LD50 is higher than 2000 mg/kg. CONCLUSIONS: HEX, DCM, and MeOH extracts showed significant antinociceptive activity, and DHS was identified as one of bioactive compounds without producing sedative, neurotoxic or gastric damage effects, as possible adverse effects reported for analgesic drugs. A role of opioid and GABAA neurotransmission appears to be involved as mechanisms of action of DHS, suggesting its potential for pain therapy and reinforcing the traditional use of B. arborea.

9.
Chin J Nat Med ; 20(6): 473-480, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35750386

RESUMO

Five new polycyclic polyprenylated acylphloroglucinols (1-5), ascyrones A-E, and four known compounds (6-9) were isolated from the aerial parts of Hypericum ascyron. All of the isolates containing a bicyclo[3.3.1]nonane-2,4,9-trione core and a benzoyl group, belonged to type B bicyclic polyprenylated acylphloroglucinols (BPAPs). Their structures and absolute configurations were established based on spectroscopic analyses and calculated electronic circular dichroism (ECD) data. The anti-inflammatory, neuroprotective and cytotoxicity activities of compounds 1-4 and 6-9 were evaluated. Compound 6 exhibited obvious anti-inflammatory activity in lipopolysaccharide (LPS)-induced RAW264.7 cells. Compounds 1 and 9 exhibited slight cytotoxicity against Hep3B cells. Meanwhile, compound 1 showed mild neuroprotective activity against corticosterone (CORT)-induced PC12 cell damage at 10 µmol·L-1.


Assuntos
Hypericum , Animais , Anti-Inflamatórios/farmacologia , Hypericum/química , Estrutura Molecular , Células PC12 , Floroglucinol/química , Floroglucinol/farmacologia , Ratos
10.
Addict Biol ; 27(4): e13182, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35754106

RESUMO

Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro-inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non-treatment-seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2 weeks of medication. At study mid-point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline-compounds (Cho), myo-inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast-treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast-treated participants had nominally lower C-reactive protein levels at visit 2 and nominally lower TNF-α/IL-10 ratios, relative to placebo. C-reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro-longitudinal ibudilast treatment may induce peripheral and putative central anti-inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti-inflammatory component to the therapeutic action of ibudilast.


Assuntos
Alcoolismo , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/tratamento farmacológico , Alcoolismo/metabolismo , Animais , Ácido Aspártico , Proteína C-Reativa , Colina/metabolismo , Creatina/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inositol/metabolismo , Piridinas
11.
Pediatr Allergy Immunol ; 33(6): e13807, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35754122

RESUMO

Asthma and allergies are major health problems and exert an enormous socioeconomic burden. Besides genetic predisposition, environmental factors play a crucial role in the development of these diseases in childhood. Multiple worldwide epidemiological studies have shown that children growing up on farms are immune to allergic diseases and asthma. Farm-related exposures shape children's immune homeostasis, via mediators such as N-glycolylneuraminic acid or arabinogalactan, or by diverse environmental microbes. Moreover, nutritional factors, such as breastfeeding or farm milk and food diversity, inducing short-chain fatty acids-producing bacteria in the intestine, contribute to farm-related effects. All farm-related exposures induce an anti-inflammatory response of the innate immunity and increase the differentiation of regulatory T cells and T helper cell type 1. A better understanding of the components of the farm environment, that are protective to the development of allergy and asthma, and their underlying mechanisms, will help to develop new strategies for the prevention of allergy and asthma.


Assuntos
Asma , Hipersensibilidade , Alérgenos , Asma/epidemiologia , Asma/etiologia , Criança , Exposição Ambiental/efeitos adversos , Fazendas , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Hipersensibilidade/prevenção & controle
12.
Artigo em Inglês | MEDLINE | ID: mdl-35762551

RESUMO

Natriuretic peptide system [NPS] is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and natriuretic peptide precursor C [NPC], that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is also produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase [NEP], also known as neprilysin. Coronavirus disease 2019 [Covid-19] pandemic may lead to acute lung injury [ALI] and/or respiratory distress syndrome [ARDS]. The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of a pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in the management of Covid-19.

13.
J Ethnopharmacol ; : 115509, 2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35760257

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Paulownia tomentosa Steud., a traditional Chinese medicinal plant, was used for many centuries in Chinese herbal medicine as a component of remedies for many illnesses, including inflammatory diseases. It is a rich source of phenolic compounds, mainly geranylated flavonoids, which are currently studied for their promising biological activities. AIM OF THE STUDY: The study aimed to isolate minor geranylated flavanones and flavones from P. tomentosa fruit and evaluate their cytotoxicity and possible anti-inflammatory effects in a cell-based model of inflammation. MATERIALS AND METHODS: Chromatographic separation of chloroform portion of the ethanolic extract of P. tomentosa fruit led to the isolation of twenty-seven flavonoids (1-27), twenty-six of them geranylated with different modifications and one non-geranylated flavanone, and two phenolic compounds. Compounds were identified using UV, IR, HRMS, NMR, and CD spectroscopy. Ten of these compounds (7-10, 12, 21, 22, 24, 25, and 27) were determined to be new flavonoid derivatives obtained from a natural source for the first time. Selected compounds were analyzed for cytotoxicity and anti-inflammatory potential to affect the activation of nuclear factor κB/activator protein 1 (NF-κB/AP-1) after lipopolysaccharide (LPS) stimulation. RESULTS: All the test compounds (1-21 and 23-26) reduced the activation of NF-κB/AP-1 24 h after the addition of LPS. Eight compounds (5, 14-18, 21, and 26) were more active than prednisone, a widely used anti-inflammatory drug. However, this effect was not seen significantly on the level of TNF-α and IL-1ß, which can be explained by the plurality of possible outcomes of activation of the NF-κB pathway in cells. CONCLUSIONS: Results of the presented study confirmed that constituents from traditional Chinese medicinal plant P. tomentosa Steud. have promising anti-inflammatory activities and can serve as a potential source of inspiration for new anti-inflammatory medications.

14.
Food Res Int ; 157: 111281, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35761591

RESUMO

Atherosclerosis (AS) is the underlying condition in most cardiovascular diseases, which is blood vessel inflammation participated by many factors. Collagen hydrolysate from salmo salar skin (SCH) obtained in this study showed strong anti-inflammatory activity, protection of endothelial cell injury, antioxidant activity, and anti-platelet aggregation activity in vitro, exhibiting a great potential of attenuating AS. In this study, multifunctional peptides FAGPPGGDGQPGAK and IAGPAGPRGPSGPA, which mainly showed strong anti-inflammatory activity, were identified from SCH after separation of ultrafiltration and column chromatography. Moreover, SCH (contained anti-platelet peptides and anti-inflammatory peptides) was observed to inhibit arterial intima thickening and plaques formation in apolipoprotein E-deficient (ApoE-/-) mice fed with high-fat diets without side effects, exhibiting a comparable effect with aspirin. SCH showed combined effect on regulating serum biomarkers of inflammation (IL-6 and TNF-α), endothelial injury (MCP-1), platelet activation (TXB2 and PF4) and oxidative stress (MDA and CAT). This research suggested SCH as a potential dietary supplement for the primary prevention of AS.

15.
Food Res Int ; 157: 111444, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35761684

RESUMO

Low molecular weight sulfate glycosaminoglycan has attracted more attention recently for its great bioactivity. In the present study, a degraded sulfate glycosaminoglycan (named D-SBSG) was prepared from swimming bladder by enzymatic depolymerization, the structure characteristics of D-SBSG and its effects on blood coagulation and inflammation in vitro was investigated. HPGPC analysis showed that the molecular weight (Mw) of SBSG was 115.84 kDa, while the Mw of D-SBSG was 4.96 kDa. The bioactivities had arose dramatic differences, though its main molecule structure had little change after enzymatic degradation. Compared with heparin sodium, relatively milder anticoagulant activity in vitro, which were positively associated with molecular weight, were found in SBSG and D-SBSG. In contrast, the results of anti-inflammatory assays indicated that D-SBSG with the lower molecular weight possessed higher bioactivity than SBSG. Additionally, the D-SBSG inhibited the LPS-induced inflammatory in RAW264.7 macrophages by down-regulation of inflammatory mediators, both of NF-κB (including p65) and MAPK (including p38) signaling pathways to exert its anti-inflammatory function. These results indicated that enzymolysis is a viable strategy for degradation of sulfate glycosaminoglycan, and D-SBSG could be a promising ingredient for inflammation management.

16.
Food Chem ; 393: 133359, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35671662

RESUMO

Determination of stereochemistry and enantiomeric excess in chiral natural molecules is a research of great interest because enantiomers can exhibit different biological activities. Viniferin stilbene dimers are natural molecules present in grape berries and wine but also, in larger amount, in stalks of grapevine. Four stereoisomers of viniferin stilbene dimers (7aS,8aS)-E-ε-viniferin (1a), (7aR,8aR)-E-ε-viniferin (1b), (7aS,8aR)-E-ω-viniferin (2a), and (7aR,8aS)-E-ω-viniferin (2b) were isolated from grapevine stalks of Cabernet Sauvignon, Merlot and Sauvignon Blanc, using a combination of centrifugal partition chromatography (CPC), preparative and chiral HPLC. The structure elucidation of these molecules was achieved by NMR whereas the absolute configurations of the four stereoisomers were investigated by vibrational circular dichroism spectroscopy in combination with density functional theory (DFT) calculations. This study unambiguously established the (+)-(7aS,8aS) and (+)-(7aR,8aS) configurations for E-ε-viniferin and E-ω-viniferin, respectively. Finally, we show that Cabernet Sauvignon provided the quasi enantiopure (+)-(7aS,8aS)-E-ε-viniferin compound which presents the best anti-inflammatory and anti-oxidant activities.


Assuntos
Estilbenos , Vitis , Vinho , Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacologia , Estereoisomerismo , Estilbenos/química , Vitis/química , Vinho/análise
17.
Bioorg Chem ; 127: 105943, 2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35717801

RESUMO

Talasterone A (1), an unprecedented 6/6/5 tricyclic 13(14 â†’ 8)abeo-8,14-seco-ergostane steroid, together with two known congeners dankasterone B (2) and (14ß,22E)-9,14-dihydroxyergosta-4,7,22-triene-3,6-dione (3), were characterized from Talaromyces adpressus. The structure of 1 with absolute configuration was elucidated based on NMR spectroscopic data and ECD calculation. Compound 2 belongs to a class of unconventional 13(14 â†’ 8)abeo-ergostanes, which have been renewed via the 1,2-migration of C-13-C-14 bond to C-8. In addition, compound 1 represents the first example of ergostane with a tricyclic 13(14 â†’ 8)abeo-8,14-seco-ergostane skeleton. The proposed biosynthetic pathway was established with the support of the coisolation of the known congeners from the producing organism. It is especially noteworthy that compound 1 exhibited potent anti-inflammatory activity with an IC50 value of 8.73 ± 0.66 µM, inhibiting the NF-κB pathway and thus reducing the production of proinflammatory cytokines.

18.
Zhongguo Zhong Yao Za Zhi ; 47(11): 3038-3048, 2022 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-35718528

RESUMO

Based on the brain-gut axis, the present study investigated the effect of Huanglian Houpo Decoction(HLHPD) in the treatment of ulcerative colitis(UC) and explored the mechanism in the regulation of 5-hydroxytryptamine(5-HT), substance P(SP), and vasoactive intestinal peptide(VIP) using modern technologies and molecular docking. Sixty male C57 BL/6 J mice were randomly divided into a blank control group, a model group, a sulfasalazine(SASP) group, and high-(5.00 g·kg~(-1)), medium-(2.50 g·kg~(-1)), and low-dose(1.25 g·kg~(-1)) HLHPD groups. The UC model was induced by oral administration of water containing 3% dextran sulfate sodium salt(DSS) in mice except those in the blank control group. After HLHPD was administered for 10 days, the mice were sacrificed for sample collection. Morphological changes of colon tissues were observed by HE staining. The expression of 5-HT, SP, VIP, tumor necrosis factor α(TNF-α), interleukin-6(IL-6), and interleukin-1ß(IL-1ß) in the hypothalamus, serum, and colon was determined by the enzyme-linked immunosorbent assay(ELISA). The expression of tryptophan hydroxylase 1(TPH1), SP, and VIP in colon tissues was evaluated by immunohistochemistry. The expression of brain-gut peptide receptors, such as 5-HT3 A, neurokinin receptor 1(NK-1 R), and VIP receptor 1(VPAC1) in colon tissues was investigated by Western blot. The binding affinity of the brain-gut peptide receptors to the main components of HLHPD was analyzed by molecular docking. After HLHPD intervention, UC mice showed increased body weight, reduced DAI score and occult blood, prolonged colon, down-regulated levels of TNF-α, IL-1ß, and IL-6 in colon tissues, and relieved pathological damage in the colon. The VIP levels in the colon were significantly up-regulated in the HLHPD groups. The high-and medium-dose HLHPD could significantly down-regulated SP and 5-HT in colon tissues and 5-HT in the serum, and up-regulated the VIP in the serum. The high-dose HLHPD group could down-regulate 5-HT and up-regulate VIP in the hypothalamus. It is suggested that HLHPD can reverse the levels of brain-gut peptides in UC mice to varying degrees. Correlation analysis results suggested that the expression levels of brain-gut peptides in the hypothalamus, serum, and colon tissues were related to inflammatory factors. Molecular docking results showed that berberine, coptisine, and epiberberine were presumedly the material basis for HLHPD in regulating the levels of 5-HT3 A, NK-1 R, and VPAC1. The main components of HLHPD may reduce colonic inflammation and pathological damage of colon tissues by regulating the activity of brain-gut peptides and their receptors, thereby reducing DSS-induced colitis in mice.


Assuntos
Colite Ulcerativa , Animais , Colite Ulcerativa/tratamento farmacológico , Colo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Serotonina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Bioorg Chem ; 127: 105908, 2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35728291

RESUMO

Thirty-two novel DG F-spiroacetal ring-opening derivatives, including 24 acetylated derivatives and 8 nitrogenous derivatives, were designed and synthesized from diosgenin (DG). The cytotoxicity of the novel derivatives was evaluated by MTT assay, except for compounds 4a, 4e, 4i, 4 l, 5a and 5 h, which were potentially cytotoxic to RAW264.7 cells, all the other derivatives had no significant cytotoxicity. The NO release inhibitory activities of novel derivatives were screened by Griess method. The results showed that the anti-inflammatory activity of the DG acetylated derivatives was stronger than the nitrogenous derivatives, and 4a-4 m containing acetyl groups at the 3-position may have better anti-inflammatory effects than 5a-5 k containing free hydroxyl groups. In ELISA assay, compound 4 m exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by LPS with IC50 values 0.449 ± 0.050 µM. The results of docking experiments showed that 4 m has a good affinity for p65 protein.

20.
Eur J Med Chem ; 238: 114497, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35660249

RESUMO

A total of 31 quinoline-based derivatives were designed and synthesized to develop novel anti-inflammatory drugs. After the toxicity of synthetic compounds to RAW264.7 cells were evaluated in vitro, their anti-inflammatory activity was assessed by inhibiting lipopolysaccharide (LPS)-induced NO production levels in the RAW264.7 cells. Among the derivatives, compound f4 had the best anti-inflammatory activity, which could reduce the production of pro-inflammatory cytokines NO, IL-1ß, and TNF-α with corresponding IC50 values of 20.40 ± 0.94, 18.98 ± 0.21 and 23.48 ± 0.46 µM. Western blot showed that f4 could inhibit the expression of LPS-induced inflammatory mediators iNOS and COX-2. Molecular docking showed that f4 could also enter the PDE4B receptor binding pocket, and the cellular thermal shift assay method indicated that the PDE4B protein bound to f4 had increased stability. Meanwhile, the inhibitory effect of this compound on the PDE4B enzyme (IC50 = 0.94 ± 0.36 µM) was comparable to that of the positive drug rolipram (IC50 = 1.04 ± 0.28 µM). Finally, in vivo studies showed that f4 could improve the degree of foot swelling and knee joint pathology in adjuvant-induced arthritic rats and decrease the levels of serum inflammatory factors TNF-α and IL-1ß in a dose-dependent manner. Therefore, the development and design of quinoline-based derivatives for anti-inflammatory applications could be considered opportunities and challenges.


Assuntos
Artrite Experimental , Fator de Necrose Tumoral alfa , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Ratos , Fator de Necrose Tumoral alfa/metabolismo
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