The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates gene expression in a range of cells, including immune and epithelial cells. AhR signaling plays important roles in the immune system in both health and disease states. Tapinarof is a first-in-class small-molecule topical therapeutic AhR modulating agent launched for the treatment of psoriasis. To improve the activity and chemical stability of Tapinarof, a series of 2-phenylchromen-4-one derivatives were designed, synthesized and evaluated as novel AhR agonists. Compounds 5a, 5c, 5e and 5f potently activated AhR with an EC₅₀ value of 7, 9, 6 and 6 nmol·L^-1, respectively, which are 10-14 fold more potent than Tapinarof. Compounds 5a and 5e exhibit comparable inhibitory effects on IFN-γ production as Tapinarof. Furthermore, compounds 5a-5f exhibited favorable photochemical stability compared to Tapinarof. The compounds may eventually serve as lead compounds for the development of new AhR agonists.

Objective: To investigate the influencing factors for myopia among primary and secondary school students in Suzhou, so as to provide basis for myopia prevention and control. Methods: The students in Grade 4-12 were recruited by stratified cluster random sampling method. Gender, grade, parents＇ myopia history, outdoor activity time and video display terminal time were collected through the questionnaire of National Surveillance Program of Influencing Factors for Common Diseases and Health in Students. Uncorrected visual acuity and cycloplegic refraction were tested. Multivariate logistic regression analysis was performed to explore myopia-related factors. Results: A total of 990 questionnaires were distributed, and 882 valid questionnaires were recovered, with an effective rate of 89.09%. The prevalence rate of myopia was 78.23% ( 690 cases ). Multivariate logistic regression analysis showed that females ( OR=1.703, 95%CI: 1.173-2.474 ) , middle school students ( OR:5.597-11.949, 95%CI: 3.573-28.349 ) , both parents＇myopia ( OR=2.445, 95%CI: 1.597-3.742 ) , video display terminal time over 3 hours per day ( OR=2.026, 95%CI: 1.235-3.325 ) were risk factors for myopia; outdoor activity time over 2 hours per day ( OR: 0.493-0.510, 95%CI: 0.273-0.943 ) was a protective factor for myopia. Conclusion The prevalence of myopia among primary and secondary school students in Suzhou is 78.23%. Gender, grade, parents＇ myopia history, outdoor activity time and video display terminal time are influencing factors for myopia.

Amorphous solid dispersion (ASD) is one of the most effective formulation approaches to enhance the water solubility and oral bioavailability of poorly water-soluble drugs. However, maintenance of physical stability of amorphous drug is one of the main challenges in the development of ASD. Crystallization is a process of nucleation and crystal growth. The nucleation is the key factor that influences the physical stability of the ASD. However, a theoretical framework to describe the way to inhibit the nucleation of amorphous drug is not yet available. We reviewed the methods and theories of nucleation for amorphous drug. Meanwhile, we also summarized the research progress on the mechanism of additives influence on nucleation and environmental factors on nucleation. This review aims to enhance the better understanding mechanism of nucleation of amorphous drug and controlling over the crystal nucleation during the ASD formulation development.

Female ; Humans ; Lymphoma, T-Cell ; diagnosis ; Middle Aged ; Multiple Myeloma ; diagnosis

OBJECTIVETo investigate the changes in the expression of aquaporin 1 (AQP-1) in edematous small intestinal tissues of rats after severe burn and the effect of early enteral feeding on its expression.

METHODSNinety normal adult Wistar rats were randomly divided into normal control group (n=6), burn model group (n=42, with 30% TBSA III degrees) and early feeding group (n=42). Dry weight method, ELSIA and immunohistochemistry were used to observe and detect the water content and expression of AQP-1 in the intestinal tissue at 1, 4, 8, 12, 24, 48, and 72 h after the burns.

RESULTSIn the burn model group, the water content in the intestinal tissue increased at 4 h after the injury, reaching the peak level at 48 h; AQP-1 expression decreased at 8 h after severe burn and reached the lowest level at 48 h. AQP-1 expression level showed a significant inverse correlation to the water content (P<0.01). Compared with the burn model group, the rats in the early feeding group showed increased AQP-l expression and lessened edema in the small intestines, also demonstrating an inverse correlation between water content and AQP-l expression (P<0.01).

CONCLUSIONIntestinal AQP-1 expression gradually decreased and edema worsened in rats early after severe burn, reaching the lowest or the peak levels 48 h after the injury with an inverse correlation between them. Early enteral feeding can increase the expression of AQP-l in the small intestine to ameliorate the intestinal edema in rats with severe burn injury.

Animals ; Aquaporin 1 ; metabolism ; Burns ; diet therapy ; metabolism ; Edema ; metabolism ; Enteral Nutrition ; Female ; Intestine, Small ; metabolism ; pathology ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Time Factors

OBJECTIVETo investigate the influence of sea water immersion on inflammation and healing of the wounds in scalded rats.

METHODSOne hundred and forty-four male Wistar rats with 10% TBSA superficial partial-thickness scald were randomly divided into A (n=72, with scald) and B (n=72, with seawater immersion for 4hrs immediately after scald) groups. The serum contents of K+, Na+, Cl- were determined at 0 post-scald hour (PSH), 6PSH, 12PSH and 24 PSH with electrocyte analysis apparatus, and the changes in serum interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha) levels were determined at 0 PSH, 6PSH and 12 PSH with enzyme-linked immunosorbent assay (ELISA). The histopathological changes in the rats of the two groups were observed, and wound healing time was respectively calculated.

RESULTSThe serum contents of K+, Na+, Cl- in B group were obviously higher than those in A group. And the serum content of TNF-alpha and IL-6 in B group at 6 PSH [(140 +/- 22) ng/L, (160 +/- 41) ng/L] were significantly higher than those before scald [(29 +/- 15) ng/L, (62 +/- 17)] ng/L and in A group [(120 +/- 12) ng/L, (124 +/- 22) ng/L, ( P < 0.05)]. Compared with A group, re-epithelization of the wound differentiation in all layers of epidermis were delayed in B group, with more severe wound swelling, exudation, and topical inflammatory response. The wound healing time in B group was (16.3 +/- 1.6) d, which was obviously longer than that in A group [(14.1 +/- 1.8) d, P < 0.05)].

CONCLUSIONSea water immersion combined with scald injury can aggravate the inflammatory response of the wound and delay the wound healing process.

Animals ; Burns ; pathology ; Disease Models, Animal ; Inflammation ; Interleukin-6 ; analysis ; Male ; Rats ; Rats, Wistar ; Seawater ; adverse effects ; Tumor Necrosis Factor-alpha ; analysis ; Wound Healing

Carotid Artery, Internal/surgery* ; Carotid Stenosis/surgery* ; Endarterectomy, Carotid ; Humans ; Treatment Outcome

This study aims to investigate the effect of salvianolic acid B (Sal B), the active ingredient of Salvia miltiorrhiza, on H9C2 cardiomyocytes injured by oxygen and glucose deprivation/reperfusion (OGD/R) through regulating mitochondrial fission and fusion. The process of myocardial ischemia-reperfusion injury was simulated by establishing OGD/R model. The cell proliferation and cytotoxicity detection kit (cell counting kit-8, CCK-8) was used to detect cell viability; the kit method was used to detect intracellular reactive oxygen species (ROS), total glutathione (t-GSH), nitric oxide (NO) content, protein expression levels of mitochondrial fission and fusion, apoptosis-related detection by Western blot. Mitochondrial permeability transition pore (MPTP) detection kit and Hoechst 33342 fluorescence was used to observe the opening level of MPTP, and molecular docking technology was used to determine the molecular target of Sal B. The results showed that relative to control group, OGD/R injury reduced cell viability, increased the content of ROS, decreased the content of t-GSH and NO. Furthermore, OGD/R injury increased the protein expression levels of dynamin-related protein 1 (Drp1), mitofusions 2 (Mfn2), Bcl-2 associated X protein (Bax) and cysteinyl aspartate specific proteinase 3 (caspase 3), and decreased the protein expression levels of Mfn1, increased MPTP opening level. Compared with the OGD/R group, it was observed that Sal B had a protective effect at concentrations ranging from 6.25 to 100 μmol·L^-1. Sal B decreased the content of ROS, increased the content of t-GSH and NO, and Western blot showed that Sal B decreased the protein expression levels of Drp1, Mfn2, Bax and caspase 3, increased the protein expression level of Mfn1, and decreased the opening level of MPTP. In summary, Sal B may inhibit the opening of MPTP, reduce cell apoptosis and reduce OGD/R damage in H9C2 cells by regulating the balance of oxidation and anti-oxidation, mitochondrial fission and fusion, thereby providing a scientific basis for the use of Sal B in the treatment of myocardial ischemia reperfusion injury.

AIM:To observe the changes of autophagy-related indexes during endoplasmic reticulum stress (ERS) induced by dithiothreitol (DTT) and its effect on apoptosis in human normal hepatocytes.METHODS:LO2 cells were treated with DTT at 2.0 mmol/L for 0, 6, 12 and 24 h to induce ERS.The expression of glucose-regulated protein 78 (GRP78) , protein kinase R-like endoplasmic reticulum kinase (PERK) , activating transcription factor 4 (ATF4) , C/EBP homologous protein (CHOP) , autophagy-related gene 12 (Atg12) , autophagy-related gene 5 (Atg5) and microtubule-associated protein 1 light chain 3 (LC3) at mRNA and protein levels was determined by real-time PCR and Western blot.The apoptosis was analyzed by flow cytometry.The formation of autophagosomes was observed under transmission electron microscope.After the LO2 cells were pretreated with rapamycin at 400 nmol/L for 1 h and treated with DTT at 2.0mmol/L for 24 h, the effect of rapamycin pretreatment on the apoptosis was analyzed by flow cytometry.RESULTS:After treatment with DTT at 2.0 mmol/L for 6, 12 and 24 h, the mRNA and protein levels of GRP78, PERK, ATF4, CHOP, Atg12, Atg5 and LC3 in the LO2 cells were significantly higher than those in 0 h group (P<0.05).At the same time, the ratio of LC3Ⅱ/LC3Ⅰwas also increased after DTT treatment (P<0.05).Observation under transmission electron microscope showed that autophagosomes were found in the LO2 cells treated with DTT for 6, 12 and 24 h.After DTT treatment for 6, 12 and 24 h, the apoptosis rate of LO2 cells was significantly higher than that in DTT 0 h group, while the apoptosis induced by DTT was significantly decreased after rapamycin pretreatment (P<0.05).CONCLUSION:ERS induces autophagy and rapamycin pretreatment alleviates the apoptosis of LO2 cells to some extent.

AIM:To investigate the effect of SET7/9 (SET domain containing 7/9) -mediated endoplasmic reticulum stress (ERS) on protein kinase R-like endoplasmic reticulum kinase (PERK) signaling pathway, and to explore the mechanisms of arsenic-induced hepatocyte apoptosis.METHODS:Human liver LO2 cells were divided into control group, arsenic poisoning model group, negative transfection group and SET7/9 siRNA transfection group.The apoptosis of the LO2 cells in each group was analyzed by flow cytometry.The protein levels of SET7/9, glucose-regulated protein 78 (GRP78) , PERK and p-PERK in the LO2 cells of each group were observed by Western blot.RESULTS:Inhibition of SET7/9 expression reduced the apoptotic rate of arsenic-induced LO2 cells.Arsenic exposure increased the expression of SET7/9 in the LO2 cells.Arsenic exposure increased the protein levels of GRP78 and p-PERK in the LO2 cells, but decreased the protein levels of GRP78 and p-PERK after transfection with SET7/9 siRNA (P<0.05).CONCLUSION:Arsenic exposure induces hepatocyte apoptosis by increasing SET7/9 to activate ERS by PERK signaling pathway.