The therapeutic effect of cimifugin on atopic dermatitis in mice and its mechanism北大核心CSCD

Aim To investigate the effects of cimifugin on mouse atopic dermatitis (AD) induced by fluorescein isothiocyanate (FITC) and further explore the mechanism of its action. Methods ICR mice were randomly divided into blank group, model group, positive group (dexamethasone),low dose group,high dose group and administration group of cimifugin. FITC solution was applied to the shaved abdomen of mice in the sensitization stage, and 0.6 % FITC solution was applied to attack the ears of mice in the stimulation stage. The administration groups were given medicine for seven consecutive days. The effects of cimifugin on body weight, thymus index and spleen index of mice were detected. Ear inflammatory cell infiltration was observed by HE staining. The ear swelling of mice was measured, and Th2 cytokines IL-5,IL-13 and the key promoter of allergy IL-33 were detected by ELISA. The epithelial barrier structural proteins, filaggrin, claudinl,occludin and E-cadherin,were detected by immunohistochemistry and Western blot. Results Compared with the blank group, the model group showed significant AD symptoms. Compared with the model group, cimifugin transdermal administration group significantly reduced ear inflammatory cell infiltration,ear swelling, IL-5,IL-13 and IL-33, and significantly increased the expression of filaggrin and occludin. Conclusions Transdermal administration of cimifugin could significantly inhibit AD in mice, and its mechanism involves repairing epithelial barrier function, restoring filaggrin and occludin, inhibiting allergy promoting factor IL-33, and finally inhibiting AD inflammation. © 2023 Publication Centre of Anhui Medical University. All rights reserved.     

Exposure–effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

Aims

The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.

Methods

Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C₀), maximum concentration (C_max) and area under the concentration–time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.

Results

Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l^–1 h, P= 0.048) and C_max (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l^–1, P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l^–1 h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l^–1 h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l^–1 h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).

Conclusions

This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.     

β-methasone-containing biodegradable poly(lactide-co-glycolide) acid microspheres for intraarticular injection: effect of formulation parameters on characteristics and in vitro release

A sustained drug release system based on the injectable poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with β-methasone was prepared for localized treatment of rheumatic arthritis. The microscopy and structure of microspheres were characterized by scanning electron microscope (SEM) and Fourier transform infrared (FTIR). The effects of various formulation parameters on the properties of microspheres and in vitro release pattern of β-methasone were also investigated. The results demonstrated that increase in drug/polymer ratio led to increased particle size as well as drug release rate. Increase in PLGA concentration led to increased particle size, but decreased burst release. The drug encapsulation efficiency increased sharply by increasing polyvinyl alcohol (PVA) concentration in the aqueous phase from 1.5 to 2.0%. β-methasone release rate decreased considerately with decreasing OP (organic phase)/AP (aqueous phase) volume ratio. Stirring rate had significantly influence on the particle size and encapsulation efficiency. Independent of formulation parameters, β-methasone was slowly released from the PLGA microspheres over 11 days. The drug release profile of high drug loaded microspheres agree with Higuchi equation with a release mechanism of diffusion and erosion, that of middle drug loaded microspheres best agreed with Hixcon-Crowell equation and controlled by diffusion and erosion as well. The low drug loaded microspheres well fitted to logarithm normal distribution equation with mechanism of purely Fickian diffusion.     

Molecular mechanisms of α-crystallinopathy and its therapeutic strategy

α-B-Crystallin (CryAB, gene map locus: 11q22.3-q23.1) is a member of the small heat shock protein (HSP) family, a group of proteins that prevent protein aggregation upon exposure of a cell to heat and/or restore the biological activity of cell substrates. The missense mutation and the deletion mutation of CryAB can cause various forms of muscular disorder, including restrictive, hypertrophic, and dilated cardiomyopathies, heart failure, and skeletal muscle weakness. Collectively, these diseases constitute a rare autosomal-dominant inherited disorder called α-crystallinopathy (crystallinopathy), also known as desmin-related cardiomyopathy. The disease is a misfolded protein-related disease characterized by the formation of insoluble protein aggregates consisting of the CryAB protein in the patient's cardiomyocytes and skeletal myocytes. The details of crystallinopathy are unclear at the present time; what has been discovered concerning the disease mechanisms underlying crystallinopathy has been through experiments with genetically modified mice such as the CryAB knockout mouse and various mutant CryAB transgenic (TG) mice. Crystallinopathy can be recapitulated in TG mice by expressing the mutant CryAB Arg120Gly (R120G) protein, a causal mutation of crystallinopathy, specifically in the cardiomyocytes. CryAB R120G causes perinuclear formation of aggresomes containing preamyloid oligomer intermediates, which are wellknown as a primary toxic species in neurodegenerative disease. This suggests that crystallinopathy caused by the CryAB mutation could be considered one of the aggresomal and amyloid-related diseases. Moreover, recent findings have indicated that enhancement of HSP induction and inhibition of apoptotic cell death by mitochondrial protection may be a new therapeutic strategy for patients with crystallinopathy.     

Studies on the antinociception effect of melatonin and its mechanism in the rat

The antinociception effect of melatonin（Mel） and its mechanisms were studied on the trauma- pain model in the rat. A trauma - pain model was established in Wistar rats by combining right - hind limb amputation with 50℃ tail - flick test. The effects of Mel on central sensitization were studied through measuring the changes of the expression of c - fos （ an indicator of nociceptive transmission at the spinal level ） , subtance P（SP） and brain - derived neurotrophic factor （BDNF） in the spinal cord using immunohistochemistry. In addition, the contents of nitric oxide （NO） in brain and spinal tissues were also observed. The results showed that the immunoreactivity of BDNF and c - fos in spinal dorsal horn in injuried rats began to increase at the first day,     

Potentiation of the antitumor effect of 11-keto-β-boswellic acid by its 3-α-hexanoyloxy derivative

We recently discovered that a propionyloxy derivative of 11-keto-β-boswellic acid (PKBA) showed better anticancer potential than other boswellic acids including AKBA, encompassing the importance of acyl group at the 3-α-hydroxy position of KBA. In continuation of our previous work, other higher derivatives (with increasing alkoxy chain length at 3-α-hydroxy position) including butyryloxy (BKBA) and hexanoyloxy (HKBA) derivatives of KBA were synthesized. The respective IC₅₀ values of BKBA and HKBA in HL-60 cells were found to be 7.7 and 4.5 μg/ml. IC₅₀ value of HKBA was comparatively lower than that of BKBA, and further lower than that of the previously reported derivative (PKBA, IC₅₀ 8.7 μg/ml). In order to compare the anticancer potential of HKBA with PKBA, detailed in vitro pro-apoptotic and in vivo anticancer studies were carried out. The induction of apoptosis by HKBA was measured using various parameters including fluorescence and scanning electron microscopy, DNA fragmentation and Annexin V-FITC binding. The extent of DNA damage was measured using neutral comet assay. HKBA was further evaluated for its effect on DNA cell cycle and mitochondria where it was found to arrest cells in G₂/M phase and also induced loss of mitochondrial membrane potential. These events were associated with increased expression of cytosolic cytochrome c and cleavage of PARP. Target based studies showed that HKBA inhibited the enzymatic activity of topoisomerases I and II at low doses than that of PKBA. In vivo studies also revealed a low dose inhibitory effect of HKBA on ascitic and solid murine tumor models.     

Usnic acid and its derivatives for pharmaceutical use: a patent review (2000–2017)

Introduction: Usnic acid (UA) is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton and is commonly found in lichenized fungi of the genera Usnea and Cladonia. Usnic acid has been incorporated for years in cosmetics, perfumery, and traditional medicines. It has a wide range of bioactivities, including antimicrobial, antiviral, anticancer, anti-inflammatory properties.

Areas covered: This review covers patents on therapeutic activities of UA and its synthetic derivatives published during the period 2000–2017.

Expert opinion: UA demonstrates excellent anticancer and antimicrobial properties. However, its application was withdrawn due to acute liver toxicity reported with chronic consumption. The broad spectrum of its biological activity indicates high the variability of UA’s binding preferences. The main idea to be addressed in the future should include the synthesis of UA derivatives because these might possess increased bioactivity, bioavailability and decreased toxicity. It is noteworthy that UA derivatives possessed better antibacterial, antitubercular, and anticancer activity than the parent compound . Most importantly, UA and its analogs (to a greater extent than UA) can be useful in cancer drug treatment. They have the potential for joint application with other anticancer drugs in order to overcome drug resistance.     

Inhibitory effect of isobavachalcone on migration and invasion of Tca8113 cells and its mechanism北大核心CSCD

Aim To explore the inhibitory effect of isobavachalcone ( IBC) on migration and invasion of tongue squamous cell carcinoma Tca8113 cells and its possible mechanism. Methods Tca8113 cells were treated in different concentrations of IBC in vitro. Cell proliferation was detected by MTT; Wound healing assay and Transwell chamber assay were used to detect the ability of cell migration and invasion; Western blot was applied to detect the expression of Akt, p-Akt, MMP-2 and MMP-9 proteins. Results IBC could inhibit the proliferation of Tca8113 cells in a concentra-tion-and time-dependent manner. IBC can reduce cell migration and invasion. Western blot showed that IBC could an decrease the expression of p-Akt, MMP-2 and MMP-9 proteins in a concentration- dependent manner. However, the level of Akt was not affected by the concentration of IBC treatment. Conclusion IBC could inhibit the proliferation, migration and invasion in Tca8113 cells and its mechanism may be associated with the down-regulation of MMP-2 and MMP-9 proteins and the inhibition of phosphorylation of upstream Akt.     

Spermatogenic effect of Yacon tubers extracts and its constituents

AIM： Smallanthus sonchifolius （Yacon） has been used as a food and folk medicine in the Andes region. It was screened the pharmacological effects of a 50% ethanol extract of Yacon on spermatogenesis in rats. This study is carried out to evaluate the possibility of using Yacon tubers extracts as a fertility agent to treat infertility caused by spermatogenic disorders. METHODS： The dried, pulverized Yacon tubers were extracted with 50% ethanol at 50 ℃ for 5 h under sonication. The Yacon extracts were analyzed by using HPLC system on a Kromasil C18 column （250 mm × 4.6 mm）. The Yacon tubers extracts, chlomgenic acid and ferulic acid were administrated to rats once daily by oral gavage. The number of sperm heads in the testis was assessed by counting the number of sperm heads using slight modification of the procedure reported by Toth et al （1989）.RESULTS： After administration of chlorogenic acid and Yacon tuber extracts to rat for 5 weeks, the number of sperm in epididymis were increased by 20.33% and 34.48%, respectively. The ferulie acid which was reported as a metabolite of ehlorogenie acid and constituent of Yaeon to estimate the spermatogenie activity was also administered.[第一段]     

Contractile effect of 6β-acetoxy nortropane on human and guinea pig airways

目的：研究６β乙酰氧基去甲托烷（６βＡＮ）对支气管平滑肌的收缩作用．方法：不同ＭＲ拮抗剂对６βＡＮ作用的影响；ＨＰＬＣ法测定６βＡＮ对支气管平滑肌细胞内磷酸肌醇（ＩＰ）的影响；通过６βＡＮ对异丙肾上腺素（Ｉｓｏ）功能拮抗模型，观察６βＡＮ对Ｍ２Ｒ的作用．结果：（１）６βＡＮ对人及豚鼠气管的收缩强度大于ＡＣｈ，分别为６８和２４５倍；（２）阿托品（Ｍ１－Ｍ３）和ｐａｒａｆｌｕｏｒｏｈｅｘａｈｙｄｒｏｓｉｌａｄｉｆｅｎｉｄｏｌ（Ｍ３）抑制６βＡＮ的作用；（３）６βＡＮ引起平滑肌细胞内ＩＰ浓度升高；（４）６βＡＮ对Ｉｓｏ的功能性拮抗作用，在ｍｅｔｈｏｃｔｒａｍｉｎｅ（Ｍ２）０３μｍｏｌ·Ｌ－１时减弱或消失．结论：６βＡＮ通过激活Ｍ３Ｒ引起支气管平滑肌收缩；其对Ｉｓｏ的功能拮抗，部分是激活Ｍ２Ｒ所致．     

Synthesis of chroman-2-carboxylic acid N-(substituted)phenylamides and their inhibitory effect on nuclear factor-κB (NF-κB) activation

A series of chroman-2-carboxylic acid N-(substituted)phenylamides (2a-s, 3a-j) were synthesized. Their ability to inhibit nuclear factor-κB (NF-κB) activity was evaluated in lipopolysaccharide (LPS)-stimulated macrophage RAW 264.7 cells and their antioxidant activity was examined. NF-κB inhibition by chroman compounds was not related to their antioxidant activity. Compounds with -H, -NO₂ monosubstituents and -OCH₃, -CF₃ disubstituents on the phenyl ring were poor inhibitors of NF-kB activity. Compounds with -CH₃, -CF₃, -Cl monosubstituents or -Cl, -CH₃ disubstituents exhibited moderate to good NF-κB activity inhibition (IC₅₀: 18.2–95.8 μM). The most active NF-κB inhibitor, 2s, contained a 4-Cl (IC₅₀: 18.2 μM) substituent on the phenyl ring and was slightly more potent than the compound KL-1156 (1) (IC₅₀: 43.9 μM).     

Osteogenic effects of D(+)β-3,4-dihydroxyphenyl lactic acid (salvianic acid A,SAA) on osteoblasts and bone marrow stromal cells of intact and prednisone-treated rats

Aim:

Previous studies have shown that D(+)β-3,4-dihydroxyphenyl lactic acid (salvianic acid A, SAA) has anabolic effects on prednisone (GC)-induced osteoporosis in rats. The current study aims to investigate the molecular mechanism of SAA''s impact on osteogenesis and adipogenesis in bone marrow stromal cells in intact and GC-treated rats.

Methods:

For in vitro study, newborn rat calvaria osteoblasts (rOBs) and rat bone marrow stromal cells (rMSCs) were isolated, identified and cultured with SAA at different concentrations to evaluate SAA''s influence on osteogenesis and adipogenesis. In addition, 3-month-old Sprague-Dawley (SD) male rats were treated with distilled water, prednisone alone (3.0 mg·kg⁻¹·d⁻¹) or prednisone (3.0 mg·kg⁻¹·d⁻¹) and SAA (25 mg·kg⁻¹·d⁻¹) for 45 d. At the end point, the different groups of rMSCs were isolated by density-gradient centrifugation and cultured.

Results:

(1) At 0.1–10.0 mg/L, SAA increased ALP activity, type I collagen (Coll-I) mRNA and OPG mRNA expression and stimulated nodule mineralization of rOBs. SAA (0.5 mg/L) also significantly increased the ALP activity of rMSCs without a need for osteogenesis-inducing medium. At 5.0 mg/L, SAA decreased the number of adipocytes with less lipid droplet formation from the rMSCs, which typically undergo adipocyte induction. (2) Coll-I expression was markedly decreased, whereas lipoprotein lipase (LPL) mRNA expression increased by 98% when compared with the first generation of rMSCs in GC-treated rats. The SAA-treated rats demonstrated an over 2-fold increase in Coll-I expression when compared with intact rats and further showed a significant decrease in LPL expression when compared with GC-treated rats. When rMSCs were co-cultured with SAA (0.5 mg/L) in vitro, SAA did not affect Coll-I and LPL gene expression in intact rats but significantly increased Coll-I and decreased LPL gene expression in GC-treated rats.

Conclusion:

SAA protected bone from GC-induced bone marrow impairment by stimulating osteogenesis and depressing adipogenesis in bone marrow stromal cells both in vivo and in vitro. The data indicated that aqueous extract of Salvia miltiorrhiza, which include SAA, may serve as an active anabolic agent and a useful therapeutic strategy for the treatment of GC-associated osteoporosis.     

Synthesis and antiviral activity of 18α-glycyrrhizic acid and its esters

New esters (sulfate, nicotinates, and 4-methoxycinnamate) of 18α-glycyrrhizic acid (18α-GA) were synthesized; these were D/E-trans-isomers of natural 18β-GA (GA), which is the major triterpene glycoside in the roots of Spanish licorice and Urals licorice (Glycyrrhiza glabra L. and Gl. uralensis Fisher). Changes in the stereochemistry of the GA aglycone led to significant decreases in its anti-HIV-1 activity.     

Comparison of the protective effect of (R)-α-methylhistamine and its prodrugs on gastric mucosal damage induced by ethanol in the rat

• 1.1. The gastroprotective activity of two azomethine prodrugs of (R)-α-methylhistamine was examined in lesions induced by absolute ethanol (1 ml/rat intragastrically for 1 h).
• 2.2. Pretreatment with (R)-α-methylhistamine as well as with the prodrugs (30 and 100 mg/kg intragastrically [IG]) significantly reduced macroscopically visible lesions caused by ethanol, with protection being almost complete at 100 mg/kg.
• 3.3. Histologically, in rats pretreated with the three compounds at a dose of 100 mg/kg, the evidence of damage was rare, with the appearance of gastric mucosa being similar in the different treatment groups.
• 4.4. Present results are suggestive of a local component in the protective activity of (R)-α-methylhistamine.

     

The effect of luteolin-7-O-β-d-glucuronopyranoside on gastritis and esophagitis in rats

This study evaluated the inhibitory action of luteolin-7-O-beta-D-glucuronopyranoside, luteolin which was isolated from Salix gilgiana leaves, and omeprazole on reflux esophagitis and gastritis in rats. Reflux esophagitis and gastritis were induced surgically and by the administration of indomethacin, respectively. The intraduodenal administration of luteolin-7-O-beta-D-glucuronopyranoside decreased the ulcer index, injury area, gastric volume and acid output, and increased the gastric pH compared with luteolin. Luteolin-7-O-beta-D-glucuronopyranoside significantly decreased the size of the gastric lesions that had been induced by exposing the gastric mucosa to indomethacin. The malondialdehyde content, which is the end product of lipid peroxidation, was increased significantly after inducing of reflux esophagitis. The malondialdehyde content was decreased by Luteolin-7-O-beta-D-glucuronopyranoside but not luteolin or omeprazole. Luteolin-7-O-beta-D-glucuronopyranoside has a more potent antioxidative effect than luteolin. Luteolin-7-O-beta-D-glucuronopyranoside is a promising drug for the treatment of reflux esophagitis and gastritis.