AIMTo search for new compounds with strong anti-inflammatory activity and low gastrointestinal (GI) side effects.

METHODSA series of alpha-substituted p-(methanesulfonyl) phenyl-propenamides were synthesized. Their anti-inflammatory activities against xylene-induced mice ear swelling and carrageenan-induced rat paw edema were evaluated, and their GI side effects in rats were examined.

RESULTSTwenty-five target compounds (II1-25) were obtained, and their structures were determined by IR, 1H NMR, MS and elemental analysis. Thirteen compounds (II1,3,5,8-13,15,18,19,23) exhibited marked anti-inflammatory activity comparable to diclofenac sodium (DC) and rofecoxib (RC) in xylene-induced mice ear swelling model, and twelve compounds (II1,3,5,7,8,10-12,17,18,20,23) showed remarkable anti-inflammatory activity comparable to DC and RC in carrageenan-induced rat paw edema. Compounds II3,8,10,11,18,20 showed GI side effects less than DC (P < 0.01), and no significant difference compared with RC and CMC-Na (P > 0.05).

CONCLUSIONalpha-Substituted p-(methanesulfonyl)phenylpropenamides showed strong anti-inflammatory activity but few GI side effects and deserve to be further investigated.

Animals ; Anti-Inflammatory Agents, Non-Steroidal ; adverse effects ; chemical synthesis ; pharmacology ; therapeutic use ; Carrageenan ; Edema ; chemically induced ; drug therapy ; Mice ; Peptic Ulcer ; chemically induced ; Phenylpropionates ; adverse effects ; chemical synthesis ; pharmacology ; Rats ; Structure-Activity Relationship ; Sulfones ; adverse effects ; chemical synthesis ; pharmacology ; Xylenes

AIMTo search for new compounds with strong anti-inflammatory activity and low gastrointestinal (GI) side effects.

METHODSA series of p-(methanesulfonyl) styrene-linked cyclic ketone derivatives were synthesized. Their anti-inflammatory activities against xylene-induced mice ear swelling and carrageenan-induced rat paw edema were evaluated, and their GI side effects in the rats were examined.

RESULTSNine target compounds (ZA(1-9)) were obtained, and their structures were determined by IR, 1HNMR, MS and elemental analysis. Compared with controls diclofenac (DC) and rofecoxib (RC) , ZA(3, 5-9) showed no significant difference in anti-inflammatory activity against xylene-induced ear swelling in mice. ZA(3, 7, 8) showed potency comparable to DC and RC (P > 0.05) and ZA6 was more potent than DC and RC (P < 0.05) in the treatment of carrageenan-induced rat paw edema. ZA(3, 5-9) showed less GI side effects than DC (P < 0.05, P < 0.01) and no significant difference compared with RC (P > 0.05).

CONCLUSIONp-(Methanesulfonyl) styrene-linked cyclic ketone derivatives showed strong anti-inflammatory activity but few GI side effects and deserve to be further investigated.

Animals ; Anti-Inflammatory Agents, Non-Steroidal ; adverse effects ; chemical synthesis ; chemistry ; Carrageenan ; Edema ; chemically induced ; drug therapy ; Ketones ; chemical synthesis ; chemistry ; Mice ; Peptic Ulcer ; drug therapy ; Rats ; Structure-Activity Relationship ; Styrenes ; chemical synthesis ; chemistry

OBJECTIVETo evaluate the therapeutic potential of marrow-derived cardiac stem cell (MCSC) transplantation after myocardial infarction (MI) in rats.

METHODSMCSC were selected from the marrow mesenchymal stem cell (MMSC) of male SD rats by single-cell cloning culture. MI was induced by left anterior descending artery ligating in female SD rats. Equal volume PBS, MMSC and MCSC were transplanted at the border zone of the infarct one week after MI. Cardiac function was assessed by echocardiography at four weeks after cell transplantation. The hearts were removed and morphological changes of scar tissue were examined with HE staining and Masson trichrome staining, VEGFR-1(+) capillary vessels were labeled with immunohistochemical staining. Scar area and vessel density were measured by image analyzer. MCSC containing Y chromosome were examined using in situ fluorescent hybridization, and cardiomyocyte cTnT expression was also analyzed.

RESULTSCardiac transcription factor Nkx2.5 was expressed at low level in c-kit(+) MCSC. Four weeks after cell transplantation, left ventricular fractional shortening and ejection fraction were significantly higher while scar area was significantly lower in MCSC group compared to MMSC group and control group. cTnT was expressed in cells containing Y chromosome and these cells were connected with myocardium of recipient rats in the rats transplanted with MCSC. Vessel density around the infarcted tissue in MCSC group was similar as that in MMSC group and significantly higher than that in control group.

CONCLUSIONMSCS could effectually differentiate into functional cardiomyocytes at the border zone of the infarct, and MCSC transplantation post MI significantly improved cardiac functions and promoted angiogenesis.

Animals ; Bone Marrow Cells ; cytology ; Cell Differentiation ; Disease Models, Animal ; Female ; Myocardial Infarction ; therapy ; Myocytes, Cardiac ; transplantation ; Rats ; Rats, Sprague-Dawley ; Stem Cell Transplantation

ObjectiveThe absorption of substances into blood is mainly dependent on the mesenteric lymphatic pathway and the portal venous pathway. The substances transported via the portal venous pathway can be metabolized by the biotransformation in the liver. On the contrary, the substances in the mesenteric lymph fluid enter the blood circulation without biotransformation and can affect the body directly. Alcohol consumption is strongly linked to global health risk. Previous reports have analyzed the changes of metabolites in plasma, serum, urine, liver and feces after alcohol consumption. Whether alcohol consumption affects the metabolites in lymph fluid is still unknown. Therefore, it is particularly important to explore the changes of substances transported via the mesenteric lymphatic pathway and analyze their harmfulness after alcohol drinking. MethodsIn this study, male Wistar rats were divided into high, medium, and low-dosage alcohol groups (receiving Chinese Baijiu at 56%, 28% and 5.6% ABV, respectively) and water groups. The experiment was conducted by alcohol gavage lasting 10 d, 10 ml·kg^-1·d^-1. Then mesenteric lymph fluid was collected for non-targeted metabolomic analysis by using liquid chromatography-mass spectrometry (LC-MS) and bioinformatic analysis. Principal component analysis and hierarchical clustering were performed by using Biodeep. Meanwhile, KEGG enrichment analysis of the differential metabolites was also performed by Biodeep. MetaboAnalyst was used to analyze the relationship between the differential metabolites and diseases. ResultsThe metabolites in the mesenteric lymph fluid of the high-dosage alcohol group change the most. Based on the KEGG enrichment analysis, the pathways of differential metabolites between the high-dosage alcohol group and the control group are mainly enriched in the central carbon metabolism in cancer, bile secretion, linoleic acid metabolism, biosynthesis of unsaturated fatty acids, etc. Interestingly, in the biosynthesis of unsaturated fatty acids category, the content of arachidonic acid is increased by 7.25 times, whereas the contents of palmitic acid, oleic acid, stearic acid, arachidic acid and erucic acid all decrease, indicating lipid substances in lymph fluid are absorbed selectively after alcohol intake. It’s worth noting that arachidonic acid is closely related to inflammatory response. Furthermore, the differential metabolites are mainly related with schizophrenia, Alzheimer’s disease and lung cancer. The differential metabolites between the medium-dosage alcohol and the control group were mainly enriched in phenylalanine metabolism, valine, leucine and isoleucine biosynthesis, linoleic acid metabolism and cholesterol metabolism. The differential metabolites are mainly related to schizophrenia, Alzheimer’s disease, lung cancer and Parkinson’s disease. As the dose of alcohol increases, the contents of some metabolites in lymph fluid increase, including cholesterol, L-leucine, fumaric acid and mannitol, and the number of metabolites related to schizophrenia also tends to increase, indicatingthat some metabolites absorbed by the intestine-lymphatic pathway are dose-dependent on alcohol intake. ConclusionAfter alcohol intake, the metabolites transported via the intestinal-lymphatic pathway are significantly changed, especially in the high-dosage group. Some metabolites absorbed via the intestinal-lymphatic pathway are dose-dependent on alcohol intake. Most importantly, alcohol intake may cause inflammatory response and the occurrence of neurological diseases, psychiatric diseases and cancer diseases. High-dosage drinking may aggravate or accelerate the occurrence of related diseases. These results provide new insights into the pathogenesis of alcohol-related diseases based on the intestinal-lymphatic pathway.

Colon cancer-related anemia (CCRA) is mainly caused by systemic inflammation, intestinal bleeding, iron deficiency and chemotherapy-induced myelosuppression in colon cancer. However, the best therapeutic schedule and related mechanism on CCRA were still uncertain. Studies on blood enrichment and anti-tumor effects of combined Danggui Buxue Decoction (DBD), Fe and rhEPO based on CCRA and gut microbiota modulation were conducted in this paper. Here, CCRA model was successfully induced by subcutaneous inoculation of CT-26 and i.p. oxaliplatin, rhEPO + DBD high dosage + Fe (EDF) and rhEPO + DBD high dosage (ED) groups had the best blood enrichment effect. Attractively, EDF group also showed antitumor activity. The sequencing results of gut microbiota showed that compared to P group, the relative abundances of Lachnospiraceae and opportunistic pathogen (Odoribacter) in ED and EDF groups were decreased. Interestingly, EDF also decreased the relative abundances of cancer-related bacteria (Helicobacter, Lactococcus, Alloprevotella) and imbalance-inducing bacteria (Escherichia-Shigella and Parabacteroides) and increased the relative abundances of butyrate-producing bacteria (Ruminococcaceae_UCG-014), however, ED showed the opposite effects to EDF, this might be the reason of the smaller tumor volume in EDF group. Our findings proposed the best treatment combination of DBD, rhEPO and Fe in CCRA and provided theoretical basis and literature reference for CCRA-induced intestinal flora disorder and the regulatory mechanism of EDF.