[Introduction and implications of WHO position paper: vaccines against influenza, May 2022].

On May 13, 2022, World Health Organization(WHO) Position Paper on Influenza Vaccine (2022 edition) was published. This position paper updates information on influenza epidemiology, high risk population, the impact of immunization on disease, influenza vaccines and effectiveness and safety, and propose WHO's position and recommendation that all countries should consider implementing seasonal influenza vaccine immunization programmes to prepare for an influenza pandemic. In addition, it proposes that the influenza surveillance platform can be integrated with the surveillance of other respiratory viruses, such as SARS-CoV-2 and Respiratory Syncytial Virus. This position paper has some implications for the prevention and control of influenza and other respiratory infectious diseases in China: (1) Optimize influenza vaccine policies to facilitate the implementation of immunization services; (2) Influenza prevention and control should from the perspective of Population Medicine focus on the individual and community to integrate with "Promotion, Prevention, Diagnosis, Control, Treatment, Rehabilitation"; (3) Incorporate prevention and control of other respiratory infectious diseases such as influenza, COVID-19, respiratory syncytial virus and adenovirus, and intelligently monitor by integrating multi-channel data to achieve the goal of co-prevention and control of multiple diseases.

COX-2/PGE2 facilitates fracture healing by activating the Wnt/ß-catenin signaling pathway.

OBJECTIVE: The aim of this study was to explore the influence of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) on fracture healing by activating the Wnt/ß-catenin signaling pathway. MATERIALS AND METHODS: In this study, 36 adult Sprague-Dawley (SD) rats raised in our laboratory were selected as research objects. The rats were subjected to fracture surgery on the middle part of the right femoral shaft. Subsequently, they were randomly divided into the control group and experimental groups (including experimental group A and experimental group B). Rats in experimental group A were injected with PGE 2 or COX-2 selective inhibitor NS-398, while rats in experimental group B were injected with PGE2 (5 µmol/L). Meanwhile, rats in the control group were injected with the same amount of normal saline. After that, the transcriptional levels of PEG2, COX-2, vascular endothelial growth factor (VEGF) and ß-catenin in rats of the experimental group A, experimental group B and control group were detected via fluorescence quantitative Polymerase Chain Reaction (PCR) assay. Enzyme-linked immunosorbent assay (ELISA) and Western blotting were conducted to determine the changes in protein levels of PEG2, COX-2, VEGF and ß-catenin in rats of the experimental group A, experimental group B and control group. The expression level of VEGF in bone tissues at fracture ends of rats in the experimental group A, experimental group B and control group was observed through the hematoxylin-eosin (HE) staining. Furthermore, micro-computed tomography (CT) was employed to evaluate callus formation. RESULTS: The transcriptional and translational levels of COX-2, ß-catenin and VEGF in rats of experimental group A treated with COX-2 inhibitors were significantly down-regulated when compared with those of the control group, showing statistically significant differences (p<0.05). However, the levels of these genes were markedly elevated in the experimental group B treated with PGE2 in comparison with those in the control group, and the differences were statistically significant (p<0.05). After 6 weeks, HE staining showed that the expression level of VEGF in rats of the experimental group B was remarkably higher than that of the experimental group A (p<0.05). Micro-CT results revealed that the mean trabecular plate density (MTPD) of rats in the experimental group B (73.29±5.4) was markedly higher than the number of osteoblasts (49.6±3.9) in the experimental group A, showing a statistically significant difference (p<0.05). CONCLUSIONS: COX-2/PGE2 facilitates fracture healing by activating the Wnt/ß-catenin signaling pathway.

miR-940 promotes spinal cord injury recovery by inhibiting TLR4/NF-κB pathway-mediated inflammation.

OBJECTIVE: The aim of this study was to investigate the effects of miR-940 and Toll-like receptor 4/Nuclear Factor κB (TLR4/NF-κB) pathways on inflammatory responses and spinal cord injury (SCI). MATERIALS AND METHODS: This study first established a model of spinal cord injury in mice. The grip force measurement was used to detect the recovery of the forelimb, left forelimb and right forelimb of SCI mice. The quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of miR-940 and macrophage receptor TLR4 in SCI mice. In addition, the protein levels of TLR4 and inducible nitric oxide synthase (iNOS) in SCI mice were detected by Western blot. MiR-940 mimic was injected into the injured area of SCI mice to explore the effect of miR-940 overexpression on TLR4 and myeloperoxidase (MPO) expression as well as the protein levels of TLR4, P65 and iNOS. Furthermore, the grip strength of SCI mice with double forelimb, left forelimb and right forelimb was detected by the grip force test after miR-940 overexpression. RESULTS: Compared with the sham-operated mice, the grip strength of the forelimb, left forelimb, and right forelimb of the SCI group showed significant obstacles. Meanwhile, the expression of miR-940 was remarkably decreased in SCI mice along with significant elevation of the inflammatory response-related factors including TRL4 and iNOS. Then we injected SCI mice with miR-940 mimics into the spinal cord injury area and found that miR-940 overexpression decreased the expression levels of TLR4 and MPO. At the same time, the overexpression of miR-940 markedly decreased the protein levels of TLR4, P65, and iNOS in SCI mice. In addition, miR-940 overexpression improved the grip strength of the left and right forepaws and the simultaneous grip strength of the two claws of the SCI mice than those of the simple injury group. CONCLUSIONS: High expression of miR-940 can promote the recovery of spinal cord injury by downregulating the TLR4/NF-κB signaling pathway and inhibiting inflammation.

MicroRNA-23c inhibits articular cartilage damage recovery by regulating MSCs differentiation to chondrocytes via reducing FGF2.

OBJECTIVE: The aim of the study was to explore the role of microRNA-23c in the differentiation of marrow stromal cells (MSCs) to chondrocytes and its potential mechanism. MATERIALS AND METHODS: MSCs were first isolated from rat bone marrow for cell culture. Surface antigens of MSCs (CD29 and CD34) were identified by flow cytometry. MSCs were induced for chondrogenic differentiation in MCDM (Mesenchymal Stem Cell Chondrogenic Differentiation Medium) for 0, 3, and 7 days, respectively, followed by detection of RUNX2, microRNA-23c and FGF2 expressions by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Alcian blue staining was performed to access proteoglycan deposition in MSCs transfected with microRNA-23c mimics or inhibitor. Western blot was conducted to detect the protein expressions of ACAN and COL2A1 in MSCs. The binding condition between microRNA-23c and FGF2 was verified by dual-luciferase reporter gene assay. Finally, MSCs were co-transfected with microRNA-23c mimics and FGF2 overexpression plasmid for rescue experiments. RESULTS: On the fourth day of MSCs isolation, MSCs were in an elongated shape. Flow cytometry results showed positive expression of CD29 and negative expression of CD34, which were consistent with MSCs phenotype. QRT-PCR data elucidated that the mRNA levels of RUNX2 and FGF2 gradually increased, whereas microRNA-23c expression decreased with the prolongation of chondrogenic differentiation. Transfection of microRNA-23c mimics in MSCs remarkably elevated microRNA-23c expression. Alcian blue staining showed that microRNA-23c overexpression results in less proteoglycan deposition in MSCs than that of controls. Both mRNA and protein expressions of ACAN and COL2A1 decreased after microRNA-23c overexpression. Dual-luciferase reporter gene assay confirmed that FGF2 binds to microRNA-23c. Further Western blot results demonstrated that FGF2 expression is negatively regulated by microRNA-23c. FGF2 overexpression reversed the inhibitory effects of microRNA-23c on proteoglycan deposition, as well as expressions of ACAN and COL2A1. CONCLUSIONS: MicroRNA-23c expression decreases during chondrogenic differentiation of MSCs, which inhibits MSCs differentiation to chondrocytes by inhibiting FGF2.

[miR-30a-5p promotes the apoptosis of chondrocytes in patients with osteoarthritis by targeting protein kinase B].

Objective: To investigate the expression of miR-30a-5p in cartilage of osteoarthritis patients, and to explore its mechanism of chondrocyte apoptosis. Methods: From May 2015 to December 2016, tissue specimen of 289 patients with osteoarthritis was collected in Department of Orthopedics, Changzhou traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine.The expression of miR-30a-5p and protein kinase B(Akt) mRNA in cartilage of different patients was detected by qPCR.The apoptosis of chondrocytes was detected by Tunel method.The expression of related proteins in tissues and cells was detected by immunoblotting, and apoptosis and cell cycle were detected by flow cytometry. Results: The expression of miR-30a-5p in OA patients was significantly higher than control patients (P<0.05), but Aktwas positively related[(3.64±0.95)vs(1.03±0.31), P<0.05]. The expression of miR-30a-5p in cartilage of OA patients was negatively correlated with Akt mRNA expression (r=0.729 3, P<0.001), but it had a positive correlation with the apoptotic rate (r=0.847 5, P<0.001). miR-30a-5p targets negative regulation of Akt gene expression in SW1353 cells, and the expression of p-Akt, IkB-α, p-IkB-α, p65, p-p65 and mTOR and p-mTOR were significantly down-regulated by miR-30a-5p (P<0.05). Compared with normal SW1353 cells, the apoptosis rate of SW1353 cells which was transfected with miR-30a-5p-mimics increased by 9.65 times, G0/G1 phase cells increased by 1.37 times, S phase cells decreased by 60.94%, G2/M phase cells decreased 19.53%. Conclusion: miR-30a-5p is highly expressed in cartilage of osteoarthritis patients, and its high expression can block chondrocytes in G0/G1 phase by targeting Akt gene, and induce apoptosis of chondrocytes.

[Efficacy and safety of CTD and PCD regimens in treatment of patients with newly diagnosed multiple myeloma].

Objective: To observe the efficacy and safety of CTD (cyclophosphamide, thalidomide, dexamethasone) and PCD (bortezomib, cyclophosphamide, dexamethasone) regimens in treatment of patients with newly diagnosed multiple myeloma (NDMM) . Methods: A retrospective analysis was carried out on 88 cases of NDMM patients admitted to our hospital from July 2013 to January 2016, including 49 cases in CTD group and 39 cases in PCD group. The outcomes of two different regimens were analyzed, including response, prognosis, and adverse events. Results: The total overall remission rates (ORR, better than PR) of CTD and PCD were 65.3% (32/49) and 84.6% (33/39) , while very good partial response (VGPR) were 30.6% (15/49) and 53.8% (21/39) , and differences were statistically significant (P=0.041, P=0.028) . The median follow-up was 11.5 (3-33) months. The median progression-free survival (PFS) was (23.0±4.5) months in CTD groups, but it was not achieved in PCD group, with statistically significant differences (P=0.050) . Medial overall survival was not achieved in both two groups, without statistically significant difference (P=0.257) . There were statistical differences between patients with minor response (MR) and patients without MR in medium OS in CTD group (P=0.005) , and there were statistical difference between patients with VGPR and without VGPR in medium OS in CTD group (P=0.042) . Infection was a common adverse event in two groups. The incidences of peripheral neuropathy and herpes zoster were markedly higher in PCD group than CTD group, and the incidences of thrombus, palpation and rash, etc., were higher in CTD group. Conclusion: Both CTD and PCD regimens were effective first-line induction chemotherapy choice for NDMM. PCD regimen is better than CTD in treatment power and deep remission.

Metabolic changes in the urine of andrographolide sodium bisulfite-treated rats.

In recent years, andrographolide sodium bisulfite (ASB) has been reported to cause acute renal failure frequently in clinical practice. We hypothesized that changes in metabolic profile could have occurred after administration of ASB. To investigate the metabolic changes caused by ASB-induced nephrotoxicity, metabonomics method was utilized to depict the urine metabolic characteristics and find the specific urine biomarkers associated with ASB-induced nephrotoxicity. Sprague-Dawley rats were randomly assigned into three experimental groups. They received a single daily injection of vehicle (0.9% sodium chloride solution) or ASB at a dose of 100 or 600 mg kg(-1) day(-1) for 7 days. Twelve-hour urine was collected after the last administration. The routine urinalysis was measured by a urine automatic analyzer while urinary metabolites were evaluated using gas chromatography/mass spectrometry. The acquired data were processed by multivariate principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal PLS-DA. After 7-day administration of ASB, the positive urine samples in protein, occult blood, and ketones were increased, presenting dose dependence. The PCA and PLS-DA models were capable of distinguishing the difference between ASB-treated group and control. Biomarkers such as 1,5-anhydroglucitol, d-erythro-sphingosine, and 2-ketoadipate were identified as the most influential factors in ASB-induced nephrotoxicity.

Propofol inhibits burn injury-induced hyperpermeability through an apoptotic signal pathway in microvascular endothelial cells

Recent studies have revealed that an intrinsic apoptotic signaling cascade is involved in vascular hyperpermeability and endothelial barrier dysfunction. Propofol (2,6-diisopropylphenol) has also been reported to inhibit apoptotic signaling by regulating mitochondrial permeability transition pore (mPTP) opening and caspase-3 activation. Here, we investigated whether propofol could alleviate burn serum-induced endothelial hyperpermeability through the inhibition of the intrinsic apoptotic signaling cascade. Rat lung microvascular endothelial cells (RLMVECs) were pretreated with propofol at various concentrations, followed by stimulation with burn serum, obtained from burn-injury rats. Monolayer permeability was determined by transendothelial electrical resistance. Mitochondrial release of cytochrome C was measured by ELISA. Bax and Bcl-2 expression and mitochondrial release of second mitochondrial-derived activator of caspases (smac) were detected by Western blotting. Caspase-3 activity was assessed by fluorometric assay; mitochondrial membrane potential (Δψm) was determined with JC-1 (a potential-sensitive fluorescent dye). Intracellular ATP content was assayed using a commercial kit, and reactive oxygen species (ROS) were measured by dichlorodihydrofluorescein diacetate (DCFH-DA). Burn serum significantly increased monolayer permeability (P<0.05), and this effect could be inhibited by propofol (P<0.05). Compared with a sham treatment group, intrinsic apoptotic signaling activation - indicated by Bax overexpression, Bcl-2 downregulation, Δψm reduction, decreased intracellular ATP level, increased cytosolic cytochrome C and smac, and caspase-3 activation - was observed in the vehicle group. Propofol not only attenuated these alterations (P<0.05 for all), but also significantly decreased burn-induced ROS production (P<0.05). Propofol attenuated burn-induced RLMVEC monolayer hyperpermeability by regulating the intrinsic apoptotic signaling pathway.

Propofol inhibits burn injury-induced hyperpermeability through an apoptotic signal pathway in microvascular endothelial cells.

Recent studies have revealed that an intrinsic apoptotic signaling cascade is involved in vascular hyperpermeability and endothelial barrier dysfunction. Propofol (2,6-diisopropylphenol) has also been reported to inhibit apoptotic signaling by regulating mitochondrial permeability transition pore (mPTP) opening and caspase-3 activation. Here, we investigated whether propofol could alleviate burn serum-induced endothelial hyperpermeability through the inhibition of the intrinsic apoptotic signaling cascade. Rat lung microvascular endothelial cells (RLMVECs) were pretreated with propofol at various concentrations, followed by stimulation with burn serum, obtained from burn-injury rats. Monolayer permeability was determined by transendothelial electrical resistance. Mitochondrial release of cytochrome C was measured by ELISA. Bax and Bcl-2 expression and mitochondrial release of second mitochondrial-derived activator of caspases (smac) were detected by Western blotting. Caspase-3 activity was assessed by fluorometric assay; mitochondrial membrane potential (Δψm) was determined with JC-1 (a potential-sensitive fluorescent dye). Intracellular ATP content was assayed using a commercial kit, and reactive oxygen species (ROS) were measured by dichlorodihydrofluorescein diacetate (DCFH-DA). Burn serum significantly increased monolayer permeability (P<0.05), and this effect could be inhibited by propofol (P<0.05). Compared with a sham treatment group, intrinsic apoptotic signaling activation - indicated by Bax overexpression, Bcl-2 downregulation, Δψm reduction, decreased intracellular ATP level, increased cytosolic cytochrome C and smac, and caspase-3 activation - was observed in the vehicle group. Propofol not only attenuated these alterations (P<0.05 for all), but also significantly decreased burn-induced ROS production (P<0.05). Propofol attenuated burn-induced RLMVEC monolayer hyperpermeability by regulating the intrinsic apoptotic signaling pathway.

An enhanced cAMP pathway is responsible for the colonic hyper-secretory response to 5-HT in acute stress rats.

5-hydroxytryptamine (5-HT) is involved in the stress-induced alteration of colonic functions, specifically motility and secretion, but its precise mechanisms of regulation remain unclear. In the present study, we have investigated the effects of 5-HT on rat colonic mucosal secretion after acute water immersion restraint stress, as well as the underlying mechanism of this phenomenon, using short circuit current recording (I(SC)), real-time polymerase chain reaction, Western blot analysis, and enzyme-linked immunosorbance assays. After 2 h of water immersion restraint stress, the baseline I(SC) and 5-HT-induced I(SC) responses of the colonic mucosa were significantly increased. Pretreatment with selective 5-HT(4) receptor antagonist, SB204070, inhibited the 5-HT-induced colonic I(SC) response by 96 % in normal rats and 91.2 % in acute-stress rats. However, pretreatment with the selective antagonist of 5-HT(3) receptor, MDL72222 or Y-25130, had no obvious effect on 5-HT-induced I(SC) responses under either set of conditions. Total protein expression of both the mucosal 5-HT(3) receptors and the 5-HT(4) receptors underwent no significant changes following acute stress. Both colonic basal cAMP levels and foskolin-induced I(SC) responses were significantly enhanced in acute stress rats. 5-HT significantly enhanced the intracellular cAMP level via 5-HT(4) receptors in the colonic mucosa from both control and stressed animals, and 5-HT-induced cAMP increase in stressed rats was not more than that in control rats. Taken together, the present results indicate that acute water immersion restraint stress enhances colonic secretory responses to 5-HT in rats, a process in which increased cellular cAMP accumulation is involved.

Emodin induces chloride secretion in rat distal colon through activation of mast cells and enteric neurons.

BACKGROUND AND PURPOSE: Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is an active component of many herb-based laxatives. However, its mechanism of action is unclear. The aim of the present study was to investigate the role of mast cells and enteric neurons in emodin-induced ion secretion in the rat colon. EXPERIMENTAL APPROACH: Short-circuit current (I(SC)) recording was used to measure epithelial ion transport. A scanning ion-selective electrode technique was used to directly measure Cl(-) flux (J(Cl)-) across the epithelium. RIA was used to measure emodin-induced histamine release. KEY RESULTS: Basolateral addition of emodin induced a concentration-dependent increase in I(SC) in colonic mucosa/submucosa preparations, EC(50) 75 µM. The effect of emodin was blocked by apically applied glibenclamide, a Cl(-) channel blocker, and by basolateral application of bumetanide, an inhibitor of the Na(+) -K(+) -2Cl(-) cotransporter. Emodin-evoked J(Cl)- in mucosa/submucosa preparations was measured by scanning ion-selective electrode technique, which correlated to the increase in I(SC) and was significantly suppressed by glibenclamide and bumetanide. Pretreatment with tetrodotoxin and the muscarinic receptor antagonist atropine had no effect on emodin-induced ΔI(SC) in mucosa-only preparations, but significantly reduced emodin-induced ΔI(SC) and J(Cl)- in mucosa/submucosa preparations. The COX inhibitor indomethacin, the mast cell stabilizer ketotifen and H(1) receptor antagonist pyrilamine significantly reduced emodin-induced ΔI(SC) in mucosa and mucosa/submucosa preparations. The H(2) receptor antagonist cimetidine inhibited emodin-induced ΔI(SC) and J(Cl)- only in the mucosa/submucosa preparations. Furthermore, emodin increased histamine release from the colonic mucosa/submucosa tissues. CONCLUSIONS AND IMPLICATIONS: The results suggest that emodin-induced colonic Cl(-) secretion involves mast cell degranulation and activation of cholinergic and non-cholinergic submucosal neurons.

Entacapone promotes cAMP-dependent colonic Cl(-) secretion in rats.

BACKGROUND: Entacapone is a promising drug used widely for the treatment of Parkinson's disease (PD) as a catechol-O-methyl transferase (COMT) inhibitor. However, entacapone has gastrointestinal side effects. The aim of this study was to investigate the effects of entacapone on the epithelial ion transport in rat distal colon, and explore the underlying mechanism. METHODS: The study was performed on freshly isolated colonic mucosa-only, submucosa-only and mucosa-submucosa preparations in rat. The short circuit current (I(SC) ) was measured to determine electrogenic ion transport, and a scanning ion-selective electrode technique (SIET) was used to directly measure Cl(-) flux across the epithelium. The content of intracellular cAMP was measured with radioimmunoassay (RIA). KEY RESULTS: Entacapone increased mucosal I(SC) in the rat distal colon. I(SC) was inhibited significantly by apical addition of diphenylamine-2,2'-dicarboxylic acid (DPC), a blocker of the Cl(-) channel, basolateral application of bumetanide, an inhibitor of Na(+) -K(+) -2Cl(-) co-transporter (NKCC), removal of Cl(-) from the bathing solution, and pretreatment with MDL 12330A, an inhibitor of adenylate cyclase. Inhibiting endogenous prostaglandin (PG) synthesis with indomethacin, and eliminating submucosal enteric neural activity with tetrodotoxin (TTX)-inhibited entacapone-evoked I(SC) increases. Similar results were also obtained when Cl(-) flux was measured with SIET. Entacapone significantly increased intracellular cAMP content, which was greatly inhibited by either indomethacin or TTX in the tissues containing submucosal plexus, and by only indomethacin in the mucosa-only preparations. CONCLUSIONS & INFERENCES: Entacapone stimulates cAMP-dependent Cl(-) secretion in the rat colon, and this process is regulated by endogenous PG and the submucosal enteric nervous system.

Involvement of NF-κB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial-mesenchymal transition of breast cancer cells.

The epithelial-mesenchymal transition (EMT) induced by chemotherapeutic agents promotes malignant tumor progression; however, the mechanism underlying the drug-induced EMT remains unclear. In this study, we reported that miR-448 is the most downregulated microRNA following chemotherapy. Suppression of miR-448 correlated with EMT induction in breast cancer in vitro and in vivo. With the use of chromatin immunoprecipitation-seq analysis, we demonstrated that miR-448 suppression induces EMT by directly targeting special AT-rich sequence-binding protein-1 (SATB1) mRNA, leading to elevated levels of amphiregulin and thereby, increasing epidermal growth factor receptor (EGFR)-mediated Twist1 expression, as well as nuclear factor κB (NF-κB) activation. On the other hand, we also found that the adriamycin-activated NF-κB directly binds the promoter of miR-448 suppressing its transcription, suggesting a positive feedback loop between NF-κB and miR-448. Furthermore, all patients who received cyclophosphamide (CP), epirubicin plus taxotere/CP, epirubicin plus 5-fluorouracil chemotherapy showed miR-448 suppression, an increased SATB1, Twist1 expression and acquisition of mesenchymal phenotypes. These findings reveal an underlying regulatory pathway, in which the autoregulation between NF-κB and miR-448 is important for restrain miR-448 suppression upon chemotherapy and may have a role in the regulation of chemotherapy-induced EMT. Disruption of the NF-κB-miR-448 feedback loop during clinical treatment may improve the chemotherapy response of human breast cancers in which EMT is a critical component.

Activation of submucosal 5-HT(3) receptors elicits a somatostatin-dependent inhibition of ion secretion in rat colon.

BACKGROUND AND PURPOSE: 5-Hydroxytryptamine (5-HT) is a key regulator of the gastrointestinal system and we have shown that submucosal neuronal 5-HT(3) receptors exerted a novel inhibitory effect on colonic ion transport. The aim of the present study was to investigate the precise mechanism(s) underlying this inhibitory effect. EXPERIMENTAL APPROACH: Mucosa/submucosa or mucosa-only preparations from rat distal colon were mounted in Ussing chambers for measurement of short-circuit current (I(sc)) as an indicator of ion secretion. Somatostatin release was determined with radioimmunoassay. Intracellular cAMP content was measured with enzyme-linked immunoadsorbent assay (elisa). Immunohistochemical techniques were used to study the expression of 5-HT(3) receptors, somatostatin and somatostatin receptors in colonic tissue. KEY RESULTS: In rat distal colonic mucosa/submucosa preparations, pretreatment with 5-HT(3) receptor antagonists enhanced 5-HT-induced increases in I(sc). However, in mucosa-only preparations without retained neural elements, pretreatment with 5-HT(3) receptor antagonists inhibited 5-HT-induced DeltaI(sc). Pretreatment with a somatostatin-2 (sst(2)) receptor antagonist in mucosa/submucosa preparations augmented 5-HT-induced DeltaI(sc). Combination of sst(2) and 5-HT(3) receptor antagonists did not cause further enhancement of 5-HT-induced DeltaI(sc). Moreover, both sst(2) and 5-HT(3) receptor antagonists enhanced 5-HT-induced increase in intracellular cAMP concentration in the mucosa/submucosa preparations. 5-HT released somatostatin from rat colonic mucosa/submucosa preparations, an effect prevented by pretreatment with 5-HT(3) receptor antagonists. Immunohistochemical staining demonstrated the presence of 5-HT(3) receptors on submucosal somatostatin neurons and of sst(2) receptors on colonic mucosa. CONCLUSION AND IMPLICATIONS: Activation of neuronal 5-HT(3) receptors in the submucosal plexus of rat colon suppressed 5-HT-induced ion secretion by releasing somatostatin from submucosal neurons.

The role of P-glycoprotein/cellular prion protein interaction in multidrug-resistant breast cancer cells treated with paclitaxel.

We previously reported that treatment with P-glycoprotein (P-gp) substrates promotes in vitro invasion in multidrug-resistant (MDR) breast cancer cells. This effect is initiated by the P-gp pump function and mediated by interaction of P-gp with some unknown component(s). However, the underlying mechanism(s) remains poorly understood. Here we confirm a novel physical interaction between P-gp and cellular prion protein (PrP(c)). Blocking P-gp activity or depletion of PrP(c) inhibited paclitaxel (P-gp substrate)- induced invasion. Paclitaxel further facilitated the formation of P-gp/PrP(c) clusters residing in caveolar domains and promoted the association of P-gp with caveolin-1. Both caveolin-1 and the integrity of caveolae were required for the drug-induced invasion. In addition, the P-gp/PrP(c) complex also played an important role in anti-apoptotic activity of MCF7/Adr cells.These data provide new insights into the mode by which MDR breast cancers evade cytotoxic attacks from P-gp substrates and also suggest a role for P-gp/ PrP(c) interaction in this process.

[Effect of Curcuma zedoaria (Berg.) Bosc on the myoelectric activity of uterus in rats and study of its mechanisms].

OBJECTIVE: To investigate the effect of Curcuma zedoaria on the myoelectric activity of uterus in virgin rats and study its mech anisms. METHOD: A pair of bipolar Ag-AgCl electrodes were implanted on the serosal surface of uterus in rats to observe the effect of C. zedoaria on the myoelectric activity of uterus before and after the five agonists were injected intraperitoneally. RESULT: Decoction of C. zedoaria significantly increases the spike area, the duration and the number of bursts of action potentials of the uterine smooth muscle and its effect is related dosage. Atropine and phentolamine decreased the exciting effect of C. zedoaria, whereas verapamil, diphenhydramine and indomethacin have no effect on the excitation of C. zedoaria. CONCLUSION: C. zedoaria has obvious exciting effect on the smooth muscle of uterus in rats, and its mechanisms may be associated with M-receptor and alpha-receptor.

Low-level prenatal lead exposure and neurobehavioral development of children in the first year of life: a prospective study in Shanghai.

We used a prospective study design to assess the effects of prenatal low-level lead exposure on the development of urban, inner-city children in Shanghai. Umbilical cord blood samples wee consecutively collected from 605 live newborns. Two hundred and fifty-seven samples were excluded from the study due to clotting. Lead levels were determined on 348 cord blood samples. The geometric mean was 9.2 micrograms/dl. Based on their cord blood lead levels, infants were classified into two exposure groups: 104 in a relatively low lead group (lead levels < or = 30 percentile), and 104 in a relatively high lead group (lead levels > or = 70 percentile). Seventy-five subjects failed to complete the study, and 133 babies were included in the final cohort: 69 babies in the high lead group and 64 in the low lead group. At 3, 6, and 12 months, the Bayley Scales of Infant Development were administered and capillary blood lead levels were measured. Detailed information was obtained on a wide range of variables relevant to infant development. At all three ages, the Mental Development index (MDI) scores, adjusted for confounders, were inversely related to the infants' cord blood lead levels. The difference of the mean adjusted MDI scores between low and high lead groups was 3.4 at 3 months, 6.3 at 6 months, and 5.2 at 12 months of age. These differences were statistically significant at all time points. No significant association between cord blood lead levels and the Psychomotor Development Index (PDI) scores was detected at all three visits after adjustment for confounders. Postnatal lead levels were unrelated to concurrent developmental status. We conclude that prenatal low-level lead exposure, which is relatively common in Shanghai, is associated with an adverse developmental impact on children through the first year of life.

Umbilical cord blood lead levels in Shanghai, China.

This study was designed to determine the cord blood lead (BPb) levels of babies born in one urban area of Shanghai, and to preliminarily identify the demographic, social environment and prenatal factors which have an effect on the cord BPb concentrations. From August to November 1993, umbilical cord blood samples were obtained from 605 live newborns in the Yangpu Maternal and Child Hospital. 257 samples were excluded from measurement because of clotting. In 348 cord samples, the geometric mean of cord BPb levels was 9.2 micrograms/dl, with a 95% confidence interval of the mean 8.86-9.54 (micrograms/dl). 142 babies (40.8%) had cord BPb levels of 10 micrograms/dl or greater. As a result of this high percentage of newborns with BPb levels equal to or greater than 10 micrograms/dl, we estimate that each year in the Shanghai City about 60,000 newborns are at risk for developing neuropsychological deficiencies caused by maternal lead exposure during pregnancy. To investigate the factors affecting cord blood levels, the subjects with levels greater than the 70th percentile (10.7 micrograms/dl) (n = 104) and less than the 30th percentile (7.4 micrograms/dl) (n = 104) were selected to compare the demographic, environment and prenatal medical history. Increased BPb levels at birth were associated with maternal passive smoking, a family member being occupationally exposed to lead, proximity to major traffic way, household coal combustion, neighborhood coal combustion, low level of maternal occupations, and the increasing occurrence of having the high lead foodstuff pidan (preserved duck egg) during pregnancy. We conclude that prenatal lead exposure has become an important health issue for young children in Shanghai.