As a basic amino acid, histidine has a pK_a close to the acidity of the tumor microenvironment, thus the charge and solubility of histidine are able to vary as the pH changes. Under a neutral environment, histidine is not charged and exhibits hydrophobic properties, while it can be protonated and becomes hydrophilic when exposed to mildly acidic pH, such as tumor microenvironment. Therefore, histidine is widely used in the design of drug delivery systems to target the mildly acidic pH of tumor microenvironment. This article reviews the recent progresses of histidine-based tumor-targeting drug delivery systems, and summarizes the principles on promoting internalization and tuning drug release by taking advantage of histidine. Finally, we point out the common issues on histidine application and illustrate its future prospects.

Organic anion transporting polypeptide 1B1 (OATP1B1) is an important liver-specific uptake transporter, which mediates transport of numerous endogenous substances and drugs from blood into hepatocytes. To identify and investigate potential modulators of OATP1B1 from natural products, the effect of 21 frequently used natural compounds and extracts on OATP1B1-mediated fluorescein methotrexate transport was studied by using Chinese hamster ovary cells stably expressing OATP1B1 (CHO-OATP1B1) in 96-well plates. This method could be used for the screening of large compound libraries. Our studies showed that some flavonoids (e.g., quercetin, quercitrin, rutin, chrysanthemum flavonoids and mulberrin) and triterpenoids (e.g., glycyrrhetinic acid and glycyrrhizic acid) were inhibitors of OATP1B1 with IC50 values less than 16 µmol · L(-1). The IC50 value of glycyrrhetinic acid on OATP1B1 was comparable to its blood concentration in clinics, indicating an OATPlB1-mediated drug-drug interaction could occur. Structure-activity relationship analysis showed that flavonoids had much higher inhibitory activity than their glycosides. Furthermore, the type and length of saccharides had a significant effect on their activity. In addition, we used OATP1B1 substrates fluvastatin and rosuvastatin as probe drugs to investigate the substrate-dependent effect of several natural compounds on the function of OATP1B1 in vitro. Our results demonstrated that the effect of these natural products on the function of OATPlB1 was substrate-dependent. In summary, this study would be conducive to predicting and avoiding potential OATP1B1-mediated drug-drug and drug-food interactions and thus provide the experimental basis and guidance for rational drug use.
Animals ; Biological Products ; CHO Cells ; Cricetulus ; Drug Interactions ; Fatty Acids, Monounsaturated ; pharmacology ; Flavonoids ; pharmacology ; Indoles ; pharmacology ; Inhibitory Concentration 50 ; Organic Anion Transporters ; genetics ; metabolism ; Rosuvastatin Calcium ; pharmacology ; Structure-Activity Relationship

AIM To investigate the effect of fenofibrate and simvastatin on the serum free fatty acids of alcoholic fatty liver in rats. METHODS The rat model of alcoholic fatty liver was reproduced by chronic ethanol ingestion plus olive oil diet. The model rats were divided into three groups as follows: finofibrate treatment group(finofibrate 80 mg?kg -1 po, once a day),simvastatin treatment group (simvastatin 4 mg?kg -1 po, once a day)and control group without either above-mentioned treatment. Experimental rats were treated for four weeks and then sacrificed for blood sampling. Serum free fatty acids were analyzed by gas chromatography. RESULTS Fenofibrate significantly ameliorated the decrease in polyunsaturated fatty acids induced by ethanol [oleic acid:(38.212?7.788) ?g?L -1 vs (31.620?6.142) ?g?L -1,linoleic acid:(37.269?8.065) ?g?L -1 vs (30.254?9.063) ?g?L -1,arachidonic acid:(11.646?2.601) ?g?L -1 vs (9.012?1.236) ?g?L -1] accompanied by the improvement of the fat infiltration of the liver, but demonstrated no effect on the increase in serum saturated fatty acids by ethanol. In the contrast, simvastatin can aggravate the decrease in polyunsatrurated fatty acids and significantly increase the levels of satrurated fatty acids in serum induced by ethanol along with the pathological aggravation of alcoholic fatty liver. CONCLUSION The results of present study revealed that fenofibrate and simvastatin exerted different effect on the serum free fatty acids of alcoholic fatty liver. Polyunsatrurated fatty acids in the serum play an important role in the pathogenesis and treatment response of alcoholic fatty liver.

The exploration of drug toxicity and mechanisms is a vital component in ensuring the safe use of drugs in clinical practice, as this topic has attracted widespread concern. The intestinal flora holds great significance for drug metabolism, efficacy and mechanism, and is an instrumental metabolic organ that facilitates material information transfer and biotransformation. However, an increasing number of studies have shown that intestinal bacteria are closely related to the toxicity of specific drugs. On the one hand, drugs are transformed into toxic metabolites under the influence of intestinal bacteria, thus inducing direct drug toxicity. On the other hand, the composition and function of the intestinal flora are altered under drug influence, resulting in disruption of endogenous metabolic pathways. Consequently, this disruption compromises the intestinal barrier and affects other organs, leading to indirect drug toxicity. This review meticulously compiles recent examples of drug toxicity attributed to intestinal bacteria, explores in depth the contention that metabolic enzymes of gut microbiota may be of great influence on oral drug toxicity, and outlines prospective avenues for future research on gut microbiota and drug toxicity and mechanisms. This not only provides novel perspectives for the judicious clinical utilization of drugs but also offers insights for the safety assessment of innovative pharmaceuticals.

A gene that could be potentially involved in spermatogenesis was identified and characterized by using suppression subtractive hybridization (SSH) and rapid amplification of cDNA ends (RACE) with total RNA from type A spermatogonia and pachytene spermatocytes of rat. This gene consists of 3 433 base pairs (bp) with a complete open reading frame (ORF) of 3 171 bp and encodes a putative protein containing 1057 amino acids. The nucleotide sequence displays a 93% identity to mouse ubiquitin-activating enzyme E1, Chr Y 1 (Ube1y1) and an 82% identity to human ubiquitin-activating enzyme E1 (UBE1). The putative protein of this gene contains an ubiquitin-activating enzyme signature 1 and an ubiquitin-activating enzyme active site, which are also existed in mouse ubiquitin-activating enzyme E1, human ubiquitin-activating enzyme E1 et al. So we named this gene as Rattus norvegicus ubiquitin-activating enzyme E1 (Ube1). The sequence of Ube1 was submitted to GenBank and the accession number is EF690356. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that Ube1 was specifically expressed in testis, while its expression was not detected in heart, brain, spleen, lung, liver, muscle, kidney and ovary. Comparison of the expression of Ube1 in different developmental stages of testis and Sertoli cells (real-time PCR) indicated that Ube1 was expressed more highly in spermatogonia than in spermatocytes, spermatids and Sertoli cells. In conclusion, Ube1 is a gene encoding rat ubiquitin-activating enzyme E1 and specifically expressed in testis, which might play a key role in ubiquitin system and influence spermatogenesis.
Animals ; DNA, Complementary ; genetics ; Male ; Rats ; Real-Time Polymerase Chain Reaction ; Spermatids ; metabolism ; Spermatocytes ; metabolism ; Spermatogenesis ; genetics ; Spermatogonia ; metabolism ; Testis ; metabolism ; Ubiquitin-Activating Enzymes ; genetics ; metabolism

Objective To assess the quantitative relationship between the distribution of Himalayan marmot and its ecological environment,the terrain,the temperature and the precipitation,using remote sensing and geographic information system in Qinghai province.Methods The distribution of Himalayan marmot was located by Google Earth and ArcGIS software and by using field survey data provided by Chinese Center for Disease Control and Prevention.The corresponding ecological environment of marmot including terrain,temperature and precipitation were derived from the spatial information datasets.All results were processed according to the overlay and statistics analysis using ArcGIS software.Results Seventy-seven point twenty-seven percent(153/198) of Himalayan marmot were distributed in the area of elevation between 3000 and 4000 meters.The number of marmot reached the highest when the slope was between 0 and 17 degrees,and aspect range was between 91 and 270 degrees,180 degree was as south direction.During the period with the maximum temperature of the warmest month of 14.3-17.5 ℃,17.6-20.8 ℃ and 20.9-24.0 ℃,the distribution of marmot reached 95％(186/198) of the total area.Meanwhile,most of the marmot were presented in the area with average precipitation of 46-108 mm.Conclusions A quantitative analysis of appropriate ecological environment of Himalayan marmot in a large scope is carried uul successfully using remote sensing and geographic information system.The study indicates that spatial information technology has important applications in plague prevention and control.

Leukemia is a type of malignant tumors of hematopoietic system with the abnormal increased immature leukemia cells showing metastasis and invasion ability. Liver is one of the main targets of the leukemia cells spread to, where they may continue to proliferate and differentiate and cause liver function damage, even liver failure. Our previous studies showed that Angelica polysscharides (APS), the main effective components in Angelica sinensis of Chinese traditional medicine, was able to inhibit the proliferation and induced differentiation of the leukemia cells, however, its effect on the liver during the treatment remains elucidated. In the present study, the human leukemia NOD/SCID mouse model were established by implantation human leukemia K562 cells line, then the leukemia mouse were treated with APS, Ara-c or APS + Ara-c respectively by peritoneal injection for 14 days, to explore the effect and mechanism of the chemicals on the mouse liver. Compared to the human leukemia NOD/SCID mouse model group with the treatments of APS, Ara-c and APS + Ara-c, We found that severe liver damage and pathological changes of the liver were able to alleviate: First, the number of white blood cells in the peripheral blood was significantly lower and with less transplanted K562 leukemia cells; Second, liver function damage was alleviated as liver function tests showed that alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBiL) were significantly reduced, while the albumin (Alb) was notably increased; Third, liver antioxidant ability was improved as the activities of the antioxidant enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were significantly increased, and the contents of GSH and malonaldehyde (MDA) were decreased significantly in the liver; Fourth, the inflammation of the liver was relieved as the level of IL-1beta and IL-6, the inflammatory cytokines, were decreased significantly in the liver. Fifth, liver index was increased as the pathological observation showed that leukemia cells with diffused infiltration into the liver lobules were significantly reduced and with a remarkable increase of apoptotic positive cell rate by TUNEL test. Furthermore, the APS + Ara-c combined administration showed an even more significant positive effect. In conclusion, the APS, Ara-c therapy reduced the accumulation of leukemia cells within the liver, reduced the liver function damage and levels of inflammatory factors, improved antioxidant capacity of the liver tissue and thus alleviate the pathological changes of the liver. Moreover, the APS + Ara-c combination therapy may have an additive effect.
Angelica ; chemistry ; Animals ; Antineoplastic Combined Chemotherapy Protocols ; pharmacology ; Cell Line, Tumor ; Cytarabine ; administration & dosage ; Humans ; K562 Cells ; Leukemia ; drug therapy ; Liver ; drug effects ; Male ; Mice ; Mice, SCID ; Polysaccharides ; administration & dosage

OBJECTIVETo study the related proteins of apoptosis initiation induced by homoharringtonine (HHT) in HL-60 cells.

METHODSAfter establishment of an apoptosis initiation model induced by HHT in HL-60 cells, proteins of untreated and HHT treated HL-60 cells were extracted, and the two-dimensional polyacrylamide gel electrophoresis (2-DE) maps of the extracted proteins were established by using the immobilized pH gradient (IPG) two-dimensional electrophoresis respectively. The alteration protein spots were identified with assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and database searching.

RESULTSProteomics analysis showed that proteins including MHC class I antigen, calbindin D-28K, chloride channel protein 6, oncoprotein 18, zinc finger protein Helios and apoptosis inhibitor like protein 2 were involved in apoptosis initiation induced by HHT.

CONCLUSIONThe present study might conduce to the researches of HL-60 cells carcinogenesis and pave the way to exploit drug precursor related to HHT and initiation of apoptosis in HL-60 cells.

Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; drug effects ; Calbindins ; Chloride Channels ; analysis ; DNA-Binding Proteins ; analysis ; Electrophoresis, Gel, Two-Dimensional ; methods ; HL-60 Cells ; Harringtonines ; pharmacology ; Histocompatibility Antigens Class I ; analysis ; Humans ; Ikaros Transcription Factor ; Inhibitor of Apoptosis Proteins ; Microtubule Proteins ; Phosphoproteins ; analysis ; Proteins ; analysis ; Proteome ; analysis ; S100 Calcium Binding Protein G ; analysis ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Stathmin ; Transcription Factors ; analysis

OBJECTIVETo screen the stage-specific expression proteins during rats spermatogenesis, and to investigate the beta-actin expression and localization in the tissues of rat testicular.

METHODSHighly enriched type A spermatogonia, pachytene spermatocytes and round spermatids were isolated by STAPUT method (sedimentation velocity at unit gravity, with 2% - 4% BSA gradient in DMEM/F12 medium) respectively to get the total proteins. The difference of protein expression between the three kinds of cells was analyzed by two-dimensional electrophoresis. Then the distribution of beta-actin in rat testicular tissues was investigated using specific anti-beta-actin antibodies by immunohistochemical method.

RESULTSbeta-actin was identified as a stage-specific expression protein by two-dimensional electrophoresis. beta-actin protein was more strongly expressed in type A spermatogonia and pachytene spermatocytes, but not in round spermatids. The immunohistochemical results showed that beta-actin was mainly located in the cytoplasm of type A spermatogonia and pachytene spermatocytes and in the nuclei of nearly mature spermatids.

CONCLUSIONbeta-actin protein is a stage-specific expressed protein and may play an important role in spermatogenesis.

Actins ; biosynthesis ; Animals ; Electrophoresis, Gel, Two-Dimensional ; Male ; Mass Spectrometry ; Rats ; Rats, Sprague-Dawley ; Spermatogenesis ; physiology ; Testis ; cytology ; metabolism

OBJECTIVETo investigate the feasibility of prevention and treatment of early scar through observing the effect of feeding immunosuppressive drug cyclophosphamide on rabbit ears hypertrophic scar tissue in early stage.

METHODSThirty-two Rabbit ears were used to establish animal models for hypertrophic scar and randomly divided into four groups: group of distilled water (A), group of cyclophosphamide 5 mg x kg(-1) x d(-1) (B), group of 10 mg x kg(-1) x d(-1) (C), group of 30 mg x kg(-1) x d(-1) (D). Before animal models were built and after administration for 14 days, 28 days, leukocytes and lymphocytes were detected. After 28 days, specimens were harvested and underwent HE staining and VG staining in order to assess HI, NA, AA value changes. The data (HI, NA, AA) from each group were compared by analysis of variance, and the variance for the rank sum test when missing.

RESULTSOn the 14th day, the number of leukocytes in group A, B, C, D were (8.62 +/- 0.58) x 10(9)/L, (4.48 +/- 0.41) x 10(9)/L, (2.7 +/- 0.26) x 10(9)/L, (1.33 +/- 0.27) x 10(9)/L; the number of lymphocytes in group A, B, C, D were (3.11 +/- 0.21) x 10(9)/L, (1.67 +/- 0.16) x 10(9)/L, (0.42 +/- 0.10) x 10(9)/L, (0.40 +/- 0.09) x 10(9)/L. On the 28th day, the number of leukocytes in group A, B, C, D was (8.63 +/- 0.53) x 10(9)/L, (5.10 +/- 0.27) x 10(9)/L, (3.10 +/- 0.26) x 10(9)/L, (1.98 +/- 0.20) x 10(9)/L; the number of lymphocytes A, B, C, D was (3.06 +/- 0.16) x 10(9)/L, (2.08 +/- 0.14) x 10(9)/L, (0.96 +/- 0.19) x 10(9)/L, (0.14 +/- 0.07) x 10(9)/L. On the 14th day and 28th day, the number of leukocytes and lymphocytes in experimental groups was reduced, showing a negative relation with cyclophosphamide dose (P < 0.05). The HI in group of A, B, C, D was 3.02 +/- 0.24, 2.59 +/- 0.43, 2.06 +/- 0.19, 1.63 +/- 0.11; the AA was 40.49 +/- 2. 07, 35.29 +/- 1.99, 28.36 +/- 1.87, 24.99 +/- 1.82; the NA was 4570.5 +/- 259.3, 4222.5 +/- 199.6, 3540.3 +/- 170.3, 3341.4 +/- 228.8. The difference in HI, AA, NA between control group and any of the experimental groups was statistically significant (P < 0.01). Each group, with the dose increased, except NA content of group C and D, the HI, AA, NA was more smaller, negative correlation, the difference was statistically significant (P < 0.05).

CONCLUSIONSFeeding cyclophosphamide can inhibit leukocytes and lymphocytes number, so as to inhibit the proliferative activity of hypertrophic scar. It has significant effect on prevention of hypertrophic scar on rabbit ears in early stage.

Animals ; Cicatrix, Hypertrophic ; drug therapy ; prevention & control ; Cyclophosphamide ; pharmacology ; Ear ; pathology ; Female ; Leukocyte Count ; Leukocytes ; drug effects ; Lymphocyte Count ; Lymphocytes ; drug effects ; Male ; Rabbits