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Excess levels of chemical hepatotoxicants (alcohol, aflatoxin B1), oxidative drugs (acetaminophen) and some cytokines (ET-1, TGF-β1) can induce chronic or acute liver injury. After these, the severe hepatic disease, especially the liver fibrosis (LF) occurs without taking measures, which brings threat to human health. The dibenzocyclooctadiene lignans of S. chinensis (SCDLs) were found to act as the hepatoprotective components via blocking endothelin B receptor (ETBR). While study on its anti-LF mechanisms especially for its refined compound of schisantherin D (SC-D) is still a lack. So this study aims to investigate the anti-fibrosis effect of SC-D with in vitro and in vivo assays. Bioinformatics analysis revealed the close relations of ETBR to Smad2, Smad3, Nrf2, etc. in LF-related signaling pathways (such as TGF-β/Smad and Nrf2/ARE). Histopathological staining on livers showed the recovery trend in SC-D treated LF mice. SC-D also modulated expressions of ETBR and fibrosis or anti-oxidative related proteins (such as TIMP1, p-Smad2/3, Nrf2, Smad7, etc.) in LF mice livers. Serum levels of TNF-α, COLI, ALT, AST and LDH in SC-D treated mice were also downregulated compared with LF mice, and upregulated expression of GSH. In vitro studies, SC-D also modulated expressions of LF-related proteins to the normal tendency in LX-2 cell, while weakened its anti- LX-2 proliferation effect by transfections of si-Smad7 or si-Nrf2. Accordingly the anti-LF approach of SC-D showed relations with modulating ETBR linked fibrosis and anti-oxidative related signaling. Also, Smad7 and Nrf2 might be the key factors for SC-D mediated anti-LF effect., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Long non-coding RNAs (lncRNAs) are extensively involved in tumor development. In-depth researches on cancer-associated lncRNAs provide a theoretical basis for developing prognostic hallmarks and individualized therapeutic targets in breast cancer (BCa). This study aims to detect expression characteristics of LINC00174 in BCa and its biological role in regulating BCa cell phenotypes., Patients and Methods: LINC00174 levels in BCa and adjacent normal tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The influence of LINC00174 on pathological indicators of BCa was analyzed. In MCF-7 and MDA-MB-231 cells with LINC00174 knockdown, proliferative and migratory abilities were examined by cell counting kit-8 (CCK-8), colony formation and transwell assay, respectively. At last, molecular mechanisms of LINC00174 and its downstream gene miR-1827 in regulating BCa development were explored by Luciferase assay and rescue experiments., Results: LINC00174 was upregulated in BCa tissues than adjacent normal ones. High level of LINC00174 predicted advanced tumor staging, high metastasis rate and poor prognosis in BCa. Knockdown of LINC00174 attenuated proliferative and migratory abilities in BCa cells. MiR-1827 was the target gene binding LINC00174, showing a negative correlation between each other. Silence of miR-1827 abolished the regulatory effects of LINC00174 on proliferative and migratory abilities in BCa cells., Conclusions: LINC00174 is upregulated in BCa samples. It is closely linked to tumor staging, metastasis and prognosis in BCa. By negatively regulating miR-1827 level, LINC00174 aggravates the malignant development of BCa.

Background: A meta-analysis was conducted to examine the correlation between Helicobacter pylori infection and chronic urticaria., Methods: We searched Chinese and English databases, including CNKI, Wanfang, and Weipu, using search terms such as Helicobacter pylori infection, and chronic urticaria for articles published from the establishment of the databases to February 2021 examining the correlation between Helicobacter pylori infection and chronic urticaria. The retrieved articles contained data on Helicobacter pylori infection rates in chronic urticaria cases in different regions of the north and south in China. The retrieved articles underwent strict screenings according to inclusion and exclusion criteria. Revman5.3 software was used to perform a meta-analysis on the data of the included articles., Results: A total of 39 documents were retrieved following the searches. According to the inclusion and exclusion criteria, a total of 6 articles on 6 studies, comprising a total of 1,320 patients, were finally included in the meta-analysis. The results showed that the heterogeneity was high (I2=58%). A random-effects model was performed. An analysis of the correlation between Helicobacter pylori infection and chronic urticaria revealed significant differences between the study group and the control group [odds ratio (OR) =3.00; 95% confidence interval (CI): 1.98-4.55; P<0.00001]. The infection rate of Helicobacter pylori among chronic urticaria cases in the northern population was 16.1% (95% CI: 15.6-16.6%); of these patients 12.2% were male and 21.4% were female. The infection rate of Helicobacter pylori among chronic urticaria cases in the southern population was 18.0% (95% CI: 17.5-18.5%); of these patients, 12.3% were male and 23.1% were female. There was no significant difference in the prevalence between the male population, the female population, and the general population in the north and the south (P>0.05)., Discussion: Helicobacter pylori infection is correlated with the occurrence of chronic urticaria. There is no significant difference in the infection rate of Helicobacter pylori in chronic urticaria cases in different regions of the north and south. This study had some limitations. First, the number of patients included in each study was low, which may affect the accuracy of the results. Second, the detection methods were not uniform; thus, further research is required to support the conclusions drawn.

Ethnopharmacological Relevance: Chemical hepatotoxicity, especially alcoholic liver injury (ALI), commonly occurs in young and middle-aged people who drink heavily. ALI is extremely harmful and can induce severe disease states, such as hepatitis, liver fibrosis, cirrhosis, or liver cancer, which are similar to CCl 4 -induced liver disease states in animals. In recent studies, the pathological changes of hepatocytes and the hepatic stellate cell have shown a significant connection between endoplasmic reticulum (ER) stress and the development of liver pathology in patients. However, the detailed pathological mechanism needs to be further studied. Schisandra chinensis, (S. chinensis), a fruit-bearing vine used in Traditional Chinese Medicine (TCM), has been used to treat chronic or acute diseases, including liver disease. S. chinensis-derived lignans (SCDLs) in particular have been shown to alleviate liver pathological changes., Aim of the Study: This study sought to elucidate the mechanisms underlying SCDL-mediated hepatoprotection., Materials and Methods: We first used in silico target prediction and computational simulation methods to identify putative lignan-binding targets relative to the hepatoprotective effect. A gene microarray analysis was performed to identify differently expressed genes that might have significance in the disease pathological process. We then used histological analyses in a mice hepatotoxicity model to test the effectiveness of SCDLs in vivo, and a hepatocellular toxicity model to analyze the candidate-compound-mediated hepatoprotection and expression states of the key targets in vitro., Results: The in silico analysis results indicated that endothelin receptor B (ETBR/EDNRB) is likely a significant node during the liver pathological change process and a promising key target for the SCDL compound schisantherin D on the hepatoprotective effect; experimental studies showed that schisantherin D alleviated the EtOH- and ET-1-induced HL-7702 cell (belongs to liver parenchymal cell lines) injury ratio, decreased the expression of ETBR, and inhibited ECMs and ET-1 secretion in LX-2 cells (one form of hepatic stellate cells). SCDLs ameliorated EtOH- and CCl 4 -induced fibrosis formation in mice liver tissue. Liver tissue western blots of SCDL-treated mice showed downregulated α-SMA, ETBR, PLCβ, CHOP, Bax, and the apoptotic factors of cleaved-caspase 12, cleaved-caspase 9, and cleaved-caspase 3 hinted at an anti-apoptosis and hepatoprotective effect. The SCDL treatment also elevated serum glutathione (GSH) and reduced the serum-transforming growth factor-β1 (TGF-β1) level., Conclusion: The findings indicated that SCDLs prevent hepatotoxicity via their anti-fibrotic, anti-oxidant, and anti-apoptosis properties. ETBR may be the key factor in promoting chemical hepatotoxicity., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The complete chloroplast genome of Catalpa 'Bairihua' a hybrid variety with multi season flowering obtained from hybrid progeny of C. bungei ' Luoqiu Sihao' ( C. bungei '01' ×  C. bungei 'Changguo Qiu') and C. fargesii f. duclouxii was first sequenced with the Illumina HiSeq 2000 platform. Which was 158,210 bp in length with a typical quadruple structure and contained a large single copy (LSC: 84,928 bp) region and a small single copy (SSC: 12,664 bp) region that were separated by a pair of inverted repeats (IRa, b: 30,309 bp) region. The GC content of the whole chloroplast genome is 38.1%. A total of 130 genes was annotated in the complete chloroplast genome, including 85 protein-coding genes, 37 tRNA genes and 8rRNA genes. ML phylogenetic analysis by comparing with 39 chloroplast genomes of the Bignoniaceae indicated that Catalpa 'Bairihua' was close to Tecomaria capensis ., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: To study the effectiveness of natural killer cell-derived exosome (NK-Exos)-entrapped paclitaxel (PTX-NK-Exos) in enhancing its anti-tumor effect., Materials and Methods: The NK-Exos were isolated through ultra-high-speed centrifugation, and the PTX-NK-Exos system was constructed via electroporation. The morphology, particle size, Zeta potential and entrapment rate of PTX-NK-Exos were evaluated using transmission electron microscope (TEM), dynamic light scattering (DLS), Western blotting and high-performance liquid chromatography (HPLC), respectively. The uptake of Exos in human breast cancer MCF-7 cells was observed under a laser confocal microscope. Moreover, the effect of PTX-NK-Exos on MCF-7 cell viability was determined through methyl thiazolyl tetrazolium (MTT) assay, flow cytometry and 4',6-diamidino-2-phenylindole (DAPI) staining. The effects of PTX-NK-Exos on messenger ribonucleic acid (mRNA) and protein expressions of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax) and Caspase-3 in MCF-7 cells were detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting, respectively., Results: The NK-Exos were successfully isolated via ultra-high-speed centrifugation, and they had uniform particle size and high expression of markers for Exos. MCF-7 cells could take up Exos. The PTX-NK-Exos drug delivery system was successfully prepared using electroporation. In PTX group and NK-Exos group, the proliferation of MCF-7 cells declined, the nuclear apoptosis was evident and the apoptosis rate of MCF-7 cells rose compared with those in Control group. In PTX group and PTX-NK-Exos group, the migration of MCF-7 cells declined compared with that in Control group. According to the results of qRT-PCR and Western blotting, PTX-NK-Exos exerted an anti-tumor effect through inducing the up-regulation of Bax and Caspase-3 in the apoptotic signaling pathway in tumor cells., Conclusions: Exos isolated through ultra-high-speed centrifugation can be used to prepare the PTX-NK-Exos drug delivery system through electroporation. Drug-loaded Exos can effectively inhibit proliferation and induce apoptosis of tumor cells, thereby exerting an anti-tumor effect.

Objective: To elucidate the role of telomerase RNA elements (TERC) in alleviating osteoporosis (OP) by absorbing microRNA-217 (miRNAs-217) to regulate runt-related transcription factor 2 (RUNX2) level., Materials and Methods: The serum levels of TERC and miRNA-217 in OP patients and healthy controls were determined. During the osteogenic process, the relative levels of alkaline phosphatase (ALP), RUNX2, and Osterix were determined in hMSCs. The regulatory effects of TERC, miRNA-217, and RUNX2 on ALP and RUNX2 levels in hMSCs were examined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot. In addition, the changes in ALP activity and calcification ability in hMSCs influenced by them were assessed through ALP activity determination and alizarin red staining, respectively. The interaction of TERC/miRNA-217/RUNX2 regulatory loop and its role in influencing hMSCs osteogenesis were assessed by Dual-Luciferase Reporter Gene Assay and a series of rescue experiments, respectively., Results: The downregulated TERC and upregulated miRNA-217 were identified in the serum of the OP patients. Consistently, the downregulated TERC and upregulated miRNA-217 were discovered in in vitro osteogenic process of hMSCs. The silence of TERC, or RUNX2 downregulated ALP and RUNX2 levels, decreased ALP activity and attenuated the calcification ability in hMSCs. The overexpression of miRNA-217 gave similar results. The binding relationship in TERC/miRNA-217/RUNX2 regulatory loop was verified. At last, rescue experiments suggested that TERC accelerated hMSCs osteogenesis by absorbing miRNA-217 to upregulate RUNX2., Conclusions: The serum level of TERC is lowly expressed in OP patients. TERC influences hMSCs osteogenesis by absorbing miRNA-217 to upregulate RUNX2, thus alleviating the progression of OP.

Proinflammatory cytokine such as interleukin (IL)-1β causes inflammation of articular cartilage. In this current study, we explored the chondroprotective effects of long noncoding RNA (lncRNA) MALAT-1 on cell proliferation, apoptosis, and matrix metabolism in IL-1β-induced inflammation in articular chondrocytes. Articular chondrocytes from knee joints of normal rats were isolated and cultured, followed by identification through observation of toluidine blue and COL II immunocytochemical stainings. The proliferation of chondrocytes at passage 2 was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The inflammatory chondrocytes induced by 10 ng/mL IL-1β were observed and identified by toluidine blue and COL II immunocytochemical stainings. pcDNA 3.1 and pcDNA-MALAT-1 were transfected in the chondrocytes. Ultrastructure of chondrocytes was observed by using a transmission electron microscope. The MTT assay was carried out to evaluate chondrocyte viability. Hoechst 33258 staining and flow cytometry were adopted to assess chondrocyte apoptosis. The chondrocytes at passage 2 with the biological characteristics of chondrocytes were used for subsequent experiments. In IL-1β-treated chondrocytes, the growth rate of chondrocytes slowed down, the cells became narrow and long, the vacuoles were seen in the cells, and the morphology of the chondrocytes was irregular. The toluidine blue staining and the immunohistochemical staining of COL II became weaker. In response to IL-1β induction, articular chondrocytes showed reduced MALAT-1 expression; moreover, obvious cartilage injury was observed with decreased chondrocyte viability and Col II expression and elevated chondrocyte apoptosis, MMP-13 expression, and p-JNK expression. With the treatment of pcDNA-MALAT-1, the cartilage injury was alleviated with increased chondrocyte viability and type II collagen (Col II) expression and reduced chondrocyte apoptosis, MMP-13 expression and p-JNK expression. Taken together these results, lncRNA MALAT-1 blocked the activation of the JNK signaling pathway; thereby, IL-1β-induced inflammation in articular chondrocytes was reduced with enhanced chondrocyte proliferation and suppressed chondrocyte apoptosis and extracellular matrix degradation., (© 2019 Wiley Periodicals, Inc.)

Context: Pain, fatigue, depression, and sleep disturbance are common in patients with cancer and usually co-occur as a symptom cluster. However, the mechanism underlying this symptom cluster is unclear., Objectives: This study aimed to identify subgroups of cluster symptoms, compare demographic and clinical characteristics between subgroups, and examine the associations between inflammatory cytokines and cluster symptoms., Methods: Participants were 170 Chinese inpatients with cancer from two tertiary hospitals. Inflammatory markers including interleukin-6 (IL-6), interleukin-1 receptor antagonist, and tumor necrosis factor alpha were measured. Intergroup differences and associations of inflammatory cytokines with the cluster symptoms were examined with one-way analyses of variance and logistic regression., Results: Based on cluster analysis, participants were categorized into Subgroup 1 (all low symptoms), Subgroup 2 (low pain and moderate fatigue), or Subgroup 3 (moderate-to-high on all symptoms). The three subgroups differed significantly in Eastern Cooperative Oncology Group (ECOG) performance status, sex, residence, current treatment, education, economic status, and inflammatory cytokines levels (all P < 0.05). Compared with Subgroup 1, Subgroup 3 had a significantly poorer ECOG physical performance status and higher IL-6 levels, were more often treated with combined chemoradiotherapy, and were more likely to be rural residents. IL-6 and ECOG physical performance status were significantly associated with 1.246-fold (95% CI 1.114-1.396) and 31.831-fold (95% CI 6.017-168.385) increased risk of Subgroup 3., Conclusion: Our findings suggest that IL-6 levels are associated with cluster symptoms in cancer patients. Clinicians should identify patients at risk for more severe symptoms and formulate novel target interventions to improve symptom management., (Copyright © 2017. Published by Elsevier Inc.)

Alendronate regulates the activity of osteoclasts and healing of osteoporosis. This study investigated the effect of alendronate on bone healing and changes in the levels of cytokines. Bilateral ovaries of 10 adult female rabbits were removed surgically in aseptic condition to establish the animal model of osteoporosis. Five rabbits in group A were treated with alendronate (1.15 mg·kg -1 ·week -1 ) once a week by a stomach tube, whereas the remaining 5 in group B were treated with physiological saline. The success of the animal model establishment and the efficacy of alendronate treatment were evaluated by the sports ability score and the Basso, Beattie, and Bresnahan (BBB) score; the healing degree of osteoporosis was determined by X-ray analysis and measurement of biomechanical properties; the changes in the levels of related cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. Treatment improved dyskinesia of the animals in group A than that in group B, with significant improvement occurring in the 4th week of treatment. The BBB score of the group A animals revealed movements similar to normal, but that of the group B animals exhibited significant motor disturbance (P < 0.01). X-ray examination showed that with time, the X-ray ratings increased. Measurement of the biomechanical properties further showed that alendronate had a positive effect on osteoporosis healing. The results of ELISA and immunohistochemistry showed that the levels of ALP, BMP-2, bFGF, and IGF-1 were upregulated in group A. In conclusion, alendronate accelerated osteoporosis healing probably via certain cytokine-related mechanism.

Our study assessed the effect of bone marrow mesenchymal stem cells (BMSCs) expressing inducible hepatocyte growth factor (HGF) on the recovery of femoral head necrosis (FHN). BMSCs were isolated by density gradient centrifugation. A recombinant AdTRE-HGF was constructed as the response plasmid and Adeno-X Tet-on as the regulator vector. The regulator and the response vectors were coinfected into BMSCs and induced at 0, 200, 500, 1000, and 1200 ng/mL doxycycline (Dox). After 3 days, the concentration of HGF was determined using enzyme-linked immunosorbent assay. Forty rabbits were selected to establish the FHN model and divided into 4 experimental groups. After the rabbits were killed by ketamine overdose, the restoration of FHN was assessed. The distribution of HGF-positive cells was observed by immunohistochemical method. Enzyme-linked immunosorbent assay results showed that 1000 ng/mL Dox induced the highest HGF expression level, even higher than the 1200 ng/mL Dox induction. The highest osteonecrosis incidence and empty lacunae percentage were found in group A compared with all the other groups (all P < 0.05). Furthermore, dramatically lower osteonecrosis incidence and empty lacunae percentage were found in group C compared with those of groups B and D (all P < 0.05). A significantly higher level of HGF protein was detected in group C compared with the other groups (all P < 0.05). Our study successfully developed the AdTRE-HGF, a recombinant adenovirus carrying HGF gene, for high expression of HGF in BMSCs. Importantly, introduction of BMSCs expressing HGF successfully produced the desired therapeutic effect in reversing FHN, in a Dox-dependent manner.

Four new triterpenoid saponins, Catunaroside I [3-O-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl-arjunic acid 28-O-β-D-glucopyranoside] (1), Catunaroside J [3-O-β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucopyranosyl-arjunic acid 28-O-β-D-glucopyranoside] (2), Catunaroside K [3-O-β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucopyranosyl-tormentic acid] (3), and Catunaroside L [3-O-β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucopyranosyl-pomolic acid] (4), and two known triterpenoid saponin Arjunetoside (5) and Randiasaponin VII (6), were isolated from the stem bark of Catunaregam spinosa. Their structures were elucidated on the basis of their spectral data and chemical evidence.

The fast development of minimally invasive spine surgery in recent years is based on the advance of endoscopic microsurgery techniques, computer science and medical imaging, as well as the growing concerning of medical humanities. The concept of minimally invasive and precise targeting therapy has been penetrating into various areas of surgery, and minimal tissue damage and fewer complications are the new directions of minimally invasive spine surgery. In this article we review some advances in precise spinal surgery including percutaneous lumbar discectomy, microendoscopic discectomy, computer-assisted orthopedic surgery and robot surgery.

Angiogenesis is the formation of blood vessels from pre-existing vasculature. Excessive or uncontrolled angiogenesis is a major contributor to many pathological conditions whereas inhibition of aberrant angiogenesis is beneficial to patients with pathological angiogenesis. Catunaregin is a core of novel marine compound isolated from mangrove associate. The potential anti-angiogenesis of catunaregin was investigated in human umbilical vein endothelial cells (HUVECs) and zebrafish. HUVECs were treated with different concentrations of catunaregin in the presence or absence of VEGF. The angiogenic phenotypes including cell invasion cell migration and tube formation were evaluated following catunaregin treatment in HUVECs. The possible involvement of AKT, eNOS and ERK1/2 in catunaregin-induced anti-angiogenesis was explored using Western blotting. The anti-angiogenesis of catunaregin was further tested in the zebrafish embryo neovascularization and caudal fin regeneration assays. We found that catunaregin dose-dependently inhibited angiogenesis in both HUVECs and zebrafish embryo neovascularization and zebrafish caudal fin regeneration assays. In addition, catunaregin significantly decreased the phosphorylation of Akt and eNOS, but not the phosphorylation of ERK1/2. The present work demonstrates that catunaregin exerts the anti-angiogenic activity at least in part through the regulation of the Akt and eNOS signaling pathways.

Objective: To study the chemical constituents of Scyphiphora hydrophyllacea., Methods: The compounds were isolated and purified by repeated column chromatography on silica and Sephadex LH-20 gel and their structures were identified by spectral analysis., Results: Six compounds were identified as friedelin (1), syringic acid (2), isoscopoletin (3), fraxetol (4), casuarinondiol (5) and guaiacylglycerol-beta-ferulic acid ether (6)., Conclusion: All of these six compounds are isolated from Scyphiphora hydrophyllacea for the first time.

Several studies were conducted in cities of Liaoning Province, one of the areas of China with heavy concentrations of industry, to investigate the effects of life-style factors and environmental pollutants on lung cancer causation. A case-control study involving 1249 lung cancer patients and 1345 population-based controls was conducted in 1985-1988 in Shenyang, the capital of Liaoning. Cigarette smoking was found to be the principal cause of lung cancer in this population, accounting for 55% of the disease in males and 37% in females. There was also a significant increase in lung cancer risk associated with an overall index of indoor air pollution due to coal-burning emission. The population attributable risk (PAR) for indoor air pollution was 13% for males and 17% for females. Risks were significantly increased for workers in the non-ferrous smelter (odds ratio (OR) = 2.6, 95% CI, 1.3-5.1), chemical and drug manufacturing (OR = 3.0, 95% CI, 1.0-8.0), and the glass and pottery industry (OR = 1.6, 95% CI, 1.0-2.5). Studies in the Anshan Iron-Steel Complex showed a significant excess of lung cancer for workers exposed to a variety of dusts. A standardized proportional mortality ratio (SPMR) study of 8887 deaths during 1980-1989 among male workers of the complex indicated a 37% excess risk of lung cancer compared to residents of the city. A nested case-control study was then conducted in that complex. A total of 610 cases of lung cancer diagnosed during 1987-1993 and 959 randomly selected controls from 196 993 active and retired employees of the complex were interviewed. Historical monitoring records for dust and benzo(a)pyrene (B(a)P) were collected from 1956-1992 to calculate cumulative exposure for each person. Results suggested that risks were increased for all occupations in which there was exposure to dusts, with the highest risks seen among coke oven workers (OR = 3.5, 95% CI, 2.0-6.4) and fire-resistant brick makers (OR = 2.9, 95% CI, 1.9-4.4). Significant dose-response patterns between cumulative total dust, cumulative total B(a)P and lung cancer risk were observed. The findings suggest that smoking and environmental pollution combine to account for elevated rates of lung cancer in cities of northeastern China.

Substance P (SP) administered 40 micrograms/kg s.c. to pentobarbital-anesthetized rats induced salivation and leakage of plasma constituents into the skin, muscle, trachea, esophagus and bladder, as measured by Monastral blue B labeling of small blood vessels or by extravasation of Evans blue dye into tissues. These SP effects were inhibited by N-acetyl-neurotensin-(8-13) (Ac-NT-(8-13)) and by CP-96,345, a nonpeptide SP receptor antagonist. Intralumenal injection of Ac-NT-(8-13) or CP-96,345 into the bladder reduced SP-induced leakage of Evans blue dye but not dye leakage into the pawskin, indicating a localised drug action. Ac-NT-(8-13) appears to act directly on discrete sites in skin and in mucous membranes to functionally antagonize the inflammatory effects of SP.

Peptides of the neurotensin (NT) and xenopsin (XP) families inhibit vascular leakage in various models of tissue injury. In this study, we measured the potency of NT fragments, NT analogs and NT-(8-13) analogs for inhibition of thermal edema induced by immersion of the anesthetized rat's paw in 58 degrees C water for 1 min. The pattern of anti-edema potencies seen with sixteen NT-(8-13) analogs correlated well with the pattern of activities obtained in binding measurements to rat brain membrane preparations and to activities in isolated organ preparations. Replacement of Tyr11 with Trp in NT-(8-13) and Arg8 with D-Arg resulted in an analog [D-Arg8, Trp11]NT-(8-13) which was 5-times more potent than NT-(8-13). Substitution of D-Arg for Arg8 and Arg9 in NT-(8-13) produced analogs that retained anti-edema activity but with decreased effects on gut motility and hypotension.

Swelling, edema and leakage of proteins from the vascular compartment are immediate inflammatory responses of living tissues to local injury. Xenopsin, neurotensin (NT), NT(8-13) and NAcNT(8-13) administered to male rats anesthetized with sodium pentobarbital 60 mg/kg i.p. inhibited swelling and edema in the paw induced by immersion in 58 degrees water for 1 min. The ED50 values for xenopsin. NT, NAcNT(8-13) and NT(8-13) for reducing heat-induced edema were 0.9, 1.5, 1.9 and 2.1 nmol/kg i.v., respectively. NAcNT(8-13) was chosen as a prototype for further studies because, compared to NT, it had minimal hypotensive effects. NAcNT(8-13), 4 nmol/kg i.v., injected 10 min before mechanical injury to muscle, produced by a 4 cm midline surgical incision in the rectus abdominis, or before freeze injury to the cortex, produced by applying a cold probe (-50 degrees C) to the skull for 4 min, reduced vascular leakage, measured as area of Monastral blue staining of the injured tissues. NAcNT(8-13), 4 nmol/kg i.v., also attenuated pulmonary edema induced by epinephrine bitartrate 10 micrograms/kg i.v. The ability of NAcNT(8-13) to inhibit vascular leakage was not linked to its transient hypotensive effects and it was not blocked by alpha-helical-CRF(9-41), a putative CRF receptor antagonist, or by chlorpheniramine, a H1-histamine receptor antagonist.

Swelling, oedema, and loss of fluids and protein from the vascular compartment are immediate responses seen in living tissues after severe injury. Peptides of the corticotropin-releasing factor (CRF) superfamily have the unusual property of preventing the vascular leakage that occurs in tissues after damage. For example, CRF decreased protein extravasation, oedema and swelling in the anaesthetized rat's paw after exposure to heat or to extreme cold, in tracheal mucosa after exposure to formaldehyde, in skeletal muscle after a knife cut, and in brain cortex after freezing. The anti-inflammatory actions of CRF were independent of steroid release or hypotensive effects. CRF was a functional antagonist of inflammatory mediators such as histamine and substance P. It inhibited neurogenic inflammation, but interactions with unmyelinated sensory neurons did not account for the wide range of CRF's anti-inflammatory activities. Localized application of CRF prevented histamine-induced leaks in the hamster cheek pouch, and displaceable binding sites to iodinated CRF were found on blood vessels and on epithelial cells in close proximity to sites of vascular leakage. These results indicated peripheral sites of action. CRF may be the first example of a peptide hormone demonstrated to have potent anti-inflammatory agonist actions in vivo.

Substance P (SP), 40 micrograms/kg SC, induced protein leakage in the skin, muscle, trachea and esophagus of the anesthetized rat as measured by Monastral blue B labeling of small blood vessels. CRF, 30 micrograms/kg SC, injected 30 min before SP, decreased the SP-induced dye leakage. To locate where CRF might act, autoradiographic studies of [125I]-CRF binding to esophageal segments were conducted and displaceable binding of [125I]-CRF to submucosal elements in the esophageal epithelium were revealed, suggesting that CRF acts on selective sites to reduce vascular leakage.

Corticotropin-releasing factor (CRF) and other peptides of the corticoliberin superfamily inhibit development of edema in skin and mucosa after noxious stimuli. Here, the breadth of CRFs protective activity on small blood vessels was examined after injury to skeletal muscle or to brain cortex. Male rats (243 +/- 15 g) were anesthetized with sodium pentobarbital 60 mg/kg i.p. and Monastral blue 60 mg/kg i.v. was injected 3 min before mechanical injury to muscle produced by a 4 cm midline surgical incision in the rectus abdominis or before freeze injury to the cortex produced by applying a cold probe (-50 degrees C) to the skull for 4 min. Vascular leakage, measured as area of dye staining multiplied by its light intensity, was quantified with an image-analysis system. CRF, having the human/rat sequence, 30 micrograms/kg s.c., injected once (30 min) or twice (30 min and 10 min) before injury to muscle or to brain, inhibited the lesion size by 58% and 55%, respectively (tissues taken at 0.5 and 1 h). Microscopy showed that CRF inhibited Monastral blue labeling of small blood vessels. The ED50 (95% C.L.) of CRF for reducing vascular leakage in muscle after celiotomy was 24 (9 to 64) micrograms/kg s.c. h/rCRF injected 30 micrograms/kg s.c. 2 h before celiotomy inhibited vascular leakage after celiotomy in adrenalectomized rats and this effect was not obtained with dexamethasone phosphate, 1 mg/kg s.c. alpha-Helical CRF (9-41), a CRF receptor antagonist, attenuated the actions of CRF on celiotomy. Laser-Doppler flowmeter measurements of skeletal muscle showed that the anti-inflammatory effects of CRF occurred when there were no significant concurrent changes in blood flow. From these results, we surmise that CRF has a versatile protective effect on small blood vessels when it inhibits leakage within different vascular beds.