[Cardiac amyloidosis: pathological classification and clinical analysis of 48 cases].

Objective: To investigate the histological features and clinical manifestations in different types of cardiac amyloidosis to improve diagnostic accuracy. Methods: The histopathological features and clinical manifestations of 48 patients diagnosed with cardiac amyloidosis by Congo red stain and electron microscopy through endomyocardial biopsy were collected in West China Hospital of Sichuan University from January 2018 to December 2021. Immunohistochemical stains for immunoglobulin light chains (κ and λ) and transthyretin protein were carried out, and a review of literature was made. Results: The patients age ranged from 42 to 79 years (mean 56 years) and the male to female ratio was 1.1 to 1.0. The positive rate of endomyocardial biopsy was 97.9% (47/48), which was significantly higher than that of the abdominal wall fat (7/17). Congo red staining and electron microscopy were positive in 97.9% (47/48) and 93.5% (43/46), respectively. Immunohistochemical stains showed 32 cases (68.1%) were light chain type (AL-CA), including 31 cases of AL-λ type and 1 case of AL-κ type; 9 cases (19.1%) were transthyretin protein type (ATTR-CA); and 6 cases (12.8%) were not classified. There was no significant difference in the deposition pattern of amyloid between different types (P>0.05). Clinical data showed that ATTR-CA patients had less involvement of 2 or more organs and lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) than the other type patients (P<0.05). The left ventricular stroke volume and right ventricular ejection fraction of ATTR-CA patients were better than the other patients (P<0.05). Follow-up data of 45 patients was obtained, and the overall mean survival time was 15.6±2.0 months. Univariate survival analysis showed that ATTR-CA patients had a better prognosis, while cardiac amyloidosis patients with higher cardiac function grade, NT-proBNP >6 000 ng/L, and troponin T >70 ng/L had a worse prognosis (P<0.05). Multivariate survival analysis showed that NT-proBNP and cardiac function grade were independent prognostic factors for cardiac amyloidosis patients. Conclusions: AL-λ is the most common type of cardiac amyloidosis in this group. Congo red staining combined with electron microscopy can significantly improve the diagnosis of cardiac amyloidosis. The clinical manifestations and prognosis of each type are different and can be classified based on immunostaining profile. However, there are still a few cases that cannot be typed; hence mass spectrometry is recommended if feasible.

Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.

The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a single agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the potential for use in new regimens against drug-susceptible and drug-resistant TB.

LncRNA UCA1 regulates cervical cancer survival and EMT occurrence by targeting miR-155.

OBJECTIVE: Cervical cancer rate is increasing recently. LncRNA UCA1 plays a role in gynecological tumors, but its expression and mechanism in cervical cancer have not yet been elucidated. PATIENTS AND METHODS: The tumor tissues and adjacent tissues of cervical cancer patients were collected to measure LncRNA UCA1 and miR-155 level by Real-time PCR. The Luciferase report analyzed the relationship between LncRNA UCA1 and miR-155. HeLa cells were separated into NC group, UCA1 siRNA group, UCA1 siRNA + miR-155 inhibitor group followed by analysis of cell proliferation, invasion and migration and EMT-related genes E-cadherin and Vimentin expression by Real time PCR. RESULTS: UCA1 level was elevated and miR-155 was reduced in cervical cancer tissues with significant differences compared to adjacent tissues (p <0.05). UCA1 was negatively correlated with miR-155 level (p <0.05). Patients with high UCA1 level showed short survival time (p <0.05). Down-regulation of UCA1 can significantly inhibit cell proliferation, migration and invasion. It can also increase E-cadherin expression and decrease Vimentin expression (p <0.05). MiR-155 is a target miRNA of UCA1. MiR-155 inhibitor can significantly reverse UCA1 siRNA's effect (p <0.05). CONCLUSIONS: UCA1 expression in cervical cancer is increased and related to patient survival and miR-155 expression is reduced. Lnc-RNA UCA1 regulates EMT occurrence in cervical cancer cells by targeting miR-155.

[Effects of patient-controlled intravenous analgesia with butorphanol versus sufentanil on early postoperative rehabilitation following radical laparoscopic nephrectomy].

Objective: To investigate the effects of patient-controlled intravenous analgesia with butorphanol versus sufentanil on early postoperative rehabilitation following radical laparoscopic nephrectomy. Methods: One hundred patients undergoing radical laparoscopic nephrectomy in Affiliated Cancer Hospital of Zhengzhou University from September 2018 to February 2020 were divided into two groups (n=50) using a random number table: butorphanol patient-controlled intravenous analgesia group (group A) and sufentanil patient-controlled intravenous analgesia group (group B). Patient-controlled intravenous analgesia (PCIA) was performed at the end of surgery. The formulation of group A was butorphanol (0.15 mg/kg) and ketorolac tromethamine (180 mg) using the physiological saline at a dilution of 100 ml. The formulation of group B was sufentanil (1.5 µg/kg) and ketorolac tromethamine (180 mg) using the physiological saline at a dilution of 100 ml. At the time points of 4, 8, 24, 48 h after operation (T(1), T(2), T(3), T(4)), VAS scores at rest and cough were recorded. The incidence of remedial analgesia, the number of pressings during 48 h after the operation, the postoperative anal exhaust recovery time of the patients were recorded. Quality of recovery-40(QoR-40) scores were recorded at T(3) and T(4). Adverse reactions were recorded. Results: There was no significant difference in VAS scores at rest and cough at T(1), T(2), T(3) and T(4) between two groups (all P>0.05). There was no significant difference in the incidence of remedial analgesia and the number of pressings during 48 h after the operation between two groups (all P>0.05). The postoperative anal exhaust recovery time of the patients in group A was (32±6) h, which was lower than that in group B with statistically significant difference [(40±5) h, t=7.937, P<0.01]. The QoR-40 total scores in group A were higher than those in group B at T(3) and T(4), which were (185.8±2.5) vs (170.7±2.7), (194.8±1.9) vs (183.6±2.6), and the differences were statistically significant (t=28.878, 25.025, all P<0.01). The incidence of nausea, retching/vomiting, respiratory depression and itch during 48 h after the operation in group A were 10%, 6%, 2%, 2%, which were lower than that in group B (32%, 20%, 14%, 18%), with statistically significant difference (χ(2)=7.294, 4.322, 4.891, 5.983, all P<0.05). Conclusion: PCIA with butorphanol or sufentanil can provide satisfactory analgesia for patients undergoing radical laparoscopic nephrectomy, but butorphanol can promote postoperative rehabilitation with fewer adverse reactions.

[Bladder cancer local staging about muscle invasion: 3.0T MRI performance following transurethral resection].

OBJECTIVE: To evaluate the performance of 3.0T magnetic resonance imaging examination (MRI) for the local detecting of muscle invasive bladder cancer following transurethral resection of bladder tumor (TURBT). METHODS: Retrospective study identified 55 patients with pathology-proven bladder cancer who underwent transurethral resection of bladder tumor followed by 3.0T magnetic resonance imaging between September 2012 and April 2019 in our hospital. Two radiologists reviewed pelvic magnetic resonance imaging together and judged muscle invasive bladder cancer. Sensitivity, specificity and accuracy were calculated for the presence of muscle invasion by T2 weighted imaging (T2WI) only, diffusion-weighted imaging (DWI) only and T2WI+DWI compared with the findings at radical cystectomy as the reference standard. RESULTS: Of the 55 patients with pathological results from radical cystectomy, 3.64% (2/55) had no residual disease; 29.09% (16/55) were non-muscle invasive bladder cancer on pathology, including 13 cases in T1 and 3 cases in Ta; 34.55% (19/55) were in stage T2 depending on pathology, 25.45% (14/55) in T3, and 7.27% (4/55) in T4. The average age was 60.76 years, ranging from 42 to 82 years. There were 48 males and 7 females in our study. Before pelvic MRI examination, all the patients received transurethral resection of bladder tumor, including 16 cases taking the operation in our hospital and 39 cases in other hospitals. The interval between the pelvic MRI examination and transurethral resection of bladder tumor was more than 2 weeks in all the patients. They all underwent radical cystectomy within 1 month after the pelvic MRI examination, and no patient underwent radiotherapy or chemotherapy in our study during the interval between the MRI examination and radical cystectomy. T2WI only, DWI only, and T2WI+DWI of 3.0T magnetic resonance imaging for readers were with sensitivity: 94.59%, 83.78%, 91.89%; with specificity: 66.67%, 77.78%, 72.22% and with accuracy: 85.45%, 81.82%, 85.45%, respectively. CONCLUSION: 3.0T MRI may have a role in diagnosing muscle invasive bladder cancer following TURBT. T2WI has the advantage of detecting the location of bladder tumor, and DWI has the advantage of differentiating between the benign and malignant lesion. 3.0T MRI T2WI+DWI has a good utility in the detection of muscle invasive bladder cancer following TURBT with satisfied accuracy.

[The correlation between left atrial sphericity and thromboembolic events in patients with atrial fibrillation].

Objective: To study the correlation between left atrial sphericity (LASP) and thromboembolic events (TE) in patients with atrial fibrillation (AF). Methods: This study was conducted in patients with AF underwent radiofrequency ablation in the Department of Cardiology of First Affiliated Hospital of Zhengzhou University from January 2011 to October 2018. The AF patients with TE (study group, n=157) and the AF patients without TE (control group, n=157) were matched for age and gender. The differences of LASP and other related indexes between the two groups were compared, and the correlation between LASP and TE was analyzed by conditional logistic regression. The receiver operating characteristic (ROC) curve was drawn to analyze the diagnostic value of LASP for TE. Results: (1) The LASP in the study group was significantly higher than that in the control group [ (87.5±7.1) % vs. (82.8±6.1) %, P=0.001]. (2) Conditional logistic regression analyses showed that LASP (OR=1.10, 95%CI 1.05-1.16, P=0.001), left atrial volume index (OR=1.01, 95%CI 1.00-1.02, P=0.016) and CHA(2)D-VASc score (OR=1.77, 95%CI 1.30-2.41, P=0.001) were independently and positively correlated with TE. (3) The ROC curve analysis showed that the area under the curve (AUC) of left atrial sphericity (AUC=0.712, 95%CI 0.656-0.768, P=0.001) was larger than the AUC of either left atrial volume index (AUC=0.650, 95%CI 0.589-0.710, P=0.001) or CHA(2)D-VASc score (AUC=0.612, 95%CI 0.550-0.674, P=0.001). (4) CHA(2)D-VASc-LASP(2) score was positively correlated with TE (OR=1.95, 95%CI 1.55-2.42, P=0.001). Conclusion: LASP is independently and positively correlated with TE in patients with AF.

[Clinical significance of HLA-A, -B, -C, -DRB1, -DQB1 haplotype gene frequencies].

Objective: To analyze family-based haplotype frequencies of HLA-A, -B, -C, -DRB1 and -DQB1 genes and their clinical significance. Methods: The data of HLA genotyping in 3568 families undergoing related haploidentical transplantation between 2012 and 2017 at the First Affiliated Hospital of Soochow University were retrospectively evaluated. The HLA genotyping was performed by PCR amplification with sequence-based typing (PCR-SBT) and sequence-specific oligonucleotide probe (PCR-SSOP) methods. The family genetic analysis and haplotype frequencies were also investigated. Results: All the families were divided into 3 groups, including group1 of 1 422 entire families; group2 of 1 310 patients and either of their parents or one of their children; group3 of 836 patients and their HLA≥5/10 matched sibling donors. In the haplotypes with frequencies greater than 0.1% in group1+ group2, the frequency of A*11∶01-B*40∶01-C*03∶04-DRB1*11∶01-DQB1*03∶01, A*02∶07-B*51∶01-C*14∶02-DRB1*09:01-DQB1*03∶03 were significantly different between group1 and group2 (P=0.029, 0.033) . The frequency of A*11∶01-B*46∶01-C*01∶02∶01G-DRB1*09∶01-DQB1*03∶03 was significantly different between group1 and group3 (P=0.035) . The frequency of A*02∶01-B*40∶01-C*07∶02-DRB1*09∶01-DQB1*03∶03 was significantly different between group1 and group2 (P=0.034) , or group1 and group3 (P=0.034) . The frequency of A*24∶02-B*13∶01-C*03∶04-DRB1*12∶02-DQB1*03:01 was significantly different between group2 and group3 (P=0.046) . Conclusion: In this study, we summarize the prevalence of haplotype frequencies in terms of HLA-A, -B, -C, -DRB1 and-DQB1. Based on the database of family haplotype analysis, patients and donor candidates are sorted with matched HLA genotype while unmatched HLA haplotype. Even in patients without entire family information, HLA haplotype analysis assists in choosing the optimal related or unrelated donors.

[Retrospectively analysis on 95 postpartum hemorrhage women treated with obstetrics and gynecology in intensive care unit].

Objective: To review the clinical aspects and pathogenesis of postpartum hemorrhage (PPH) and investigate the optimal protocols for intervention. Methods: From February 2009 to December 2015, data of normal labour and casearean birth women admitted to intensive care unit (ICU) in our hospital because of hematobilia were selected. 95 patients were divided into three groups (e. g ≥500-1 000 ml, ≥1 000-1 500 ml, ≥1 500-2 500 ml and ≥2 500 ml group) according to the bleeding volume. A retrospective analysis was performed to study the pathogenesis of PPH, organ function, surgical intervention and clinical prognosis on hemorrhage. Results: The data comprised 20 504 women over the 6-year period. 95 (0.463%) of which resulted in PPH and were admitted to ICU. 9 of these patients with PPH unsurvived. The value of creatinine and urea nitrogen, the score of APACHE Ⅱ and the possibility of multiple organ dysfunction syndromethe (MODS) increased with the amount of bleeding (P<0.05). For patients with PPH caused by injury of birth canal and/or placenta factors, there was significant difference among three groups on amount of bleeding (P<0.05). For patients with surgical intervention such as vaginal packing, interventional treatment and exploratory laparotomy conducted in 6 hours, the volume of transfusion was(759±114) ml. The volume of transfusion was (2 000±829) ml and (4 999±1 699) ml in 6 to 12 hours intervention group and in greater than 12 hours intervention group, respectively. The volume of transfusion significant increased over intervention time. There was a statistically significant difference in all groups (P<0.05). Conclusions: Classified treatment should be conducted according the classification on the amount of bleeding. Patients with severe PPH and/or tendency of organ failure should be admitted to ICU. Measures for maintenance of the function of organs are necessary, while appropriate surgical intervention is also needed based on the cooperation between ICU and obstetrical department, and the cure rate could be improved.

[Analysis on the nuclear division index of peripheral blood lymphocytes in the 281 general population of Anhui, China].

OBJECTIVE: To investigate the reference range and influeing factors of the nuclear division index (NDI) of peripheral blood lymphocyte in Chinese general population in Anhui province. METHODS: We selected 281 subjects from the general poulation in Anhui province, without occupational exposure to genetic toxicants and no chronic disease history. We used questionnaires to collect occupational history, age, gender, region, body mass index, smoking, and alcohol drinking status etc. NDI was measured by cytokinesis block micronucleus assay in peripheral blood lymphocytes, and the related factors were also analyzed. And NDI was used as the dependent variable, age, gender and other factors as independent variables to conduct stepwise multiple linear regression. RESULTS: We found the data of NDI according with normal distribution, and the nuclear division index was 1.71±0.22, the minimum value was 1.10 while the maximum was 2.36. The results showed that NDI value of the males (1.67±0.20) were lower than that of the females (1.76±0.24), the difference was statistically significant (t=-3.65, P<0.001); current smokers NDI (1.66±0.18) lower than non-smokers (1.73±0.24) differences were statistically significant (t=3.06, P=0.002); the NDI of drinking groups (1.66±0.20) was lower than that of non-drinking population (1.74±0.23), the differences was statistically significant (t=3.15, P=0.002); Using multiple stepwise linear regression calibration factors and found that gender was an independent factor of NDI (ß=0.098, Sx=0.027, t=3.66, P< 0.001). CONCLUSION: We set the reference value on the nuclear division index among general population of survey areas in this study, it could provide a reference for similar studies and will provide reference for better evaluation of the effects of hazards on the body.

A medical cost estimation with fuzzy neural network of acute hepatitis patients in emergency room.

Taiwan is an area where chronic hepatitis is endemic. Liver cancer is so common that it has been ranked first among cancer mortality rates since the early 1980s in Taiwan. Besides, liver cirrhosis and chronic liver diseases are the sixth or seventh in the causes of death. Therefore, as shown by the active research on hepatitis, it is not only a health threat, but also a huge medical cost for the government. The estimated total number of hepatitis B carriers in the general population aged more than 20 years old is 3,067,307. Thus, a case record review was conducted from all patients with diagnosis of acute hepatitis admitted to the Emergency Department (ED) of a well-known teaching-oriented hospital in Taipei. The cost of medical resource utilization is defined as the total medical fee. In this study, a fuzzy neural network is employed to develop the cost forecasting model. A total of 110 patients met the inclusion criteria. The computational results indicate that the FNN model can provide more accurate forecasts than the support vector regression (SVR) or artificial neural network (ANN). In addition, unlike SVR and ANN, FNN can also provide fuzzy IF-THEN rules for interpretation.

In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis.

Nitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 against Mycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10(-7). In vitro studies and in vivo studies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.

Analysis of signaling pathways in recurrent breast cancer.

Breast cancer remains the second largest cause of death in women from cancer. By analyzing gene expression profiles in samples from breast cancer patients, 844 differentially expressed genes (DEGs) were identified in breast cancer metastasis. The 10 most significant signaling pathways identified through enrichment analysis contained DEGs were involved in oxidative phosphorylation, DNA replication, extracellular matrix-receptor interactions and others. Furthermore, survival analysis demonstrated that 5 of these signaling pathways were closely related to the survival time of breast cancer patients including basal transcription factors, cell cycle, ECM-receptor interaction, spliceosome, and DNA replication. Our findings increase the understanding of the network of signaling pathways involved in breast cancer metastasis and may provide theoretical support for further therapeutic study.

Gene expression profiling of gastric cancer.

OBJECTIVES: Gastric cancer is the second leading cause of cancer-related death worldwide. Gene expression profile facilitates the identification of molecular mechanism of gastric cancer. Previous studies mainly focused on differentially expressed genes (DEGs) without considering MicroRNAs (miRNAs) and transcription factors (TFs). Here we aim to elaborate the mechanism of gastric cancer on transcription level with microarray data from the gene expression omnibus (GEO) database. MATERIALS AND METHODS: We firstly identified DEGs between gastric cancer and normal tissues. Then the DEGs were mapped in KEGG pathway and gene ontology database to conduct functional categories enrichment analysis. MiRNAs and TFs enriched with target DEGs were also identified. RESULTS: A total of 977 DEGs were selected, including 492 down regulated and 485 overexpressed genes in gastric cancer tissue. Functional analysis revealed cell cycle, metabolism and ECM related biological processes as the significant items. Eight miRNAs and 20 TFs enriched with target DEGs were detected, including one novel miRNA (miR-557) and four novel TFs (SPI1, NFIC, SPIB and THAP1), which have not been reported to be related to gastric cancer before. All of them might contribute to the pathogenesis since they are all related to other cancers and their target genes have been reported to play important roles in gastric tumorigenesis. CONCLUSIONS: Our results may facilitate further therapeutic studies of gastric cancer.

Progress of superconducting electron cyclotron resonance ion sources at Institute of Modern Physics (IMP).

Superconducting ECR ion sources can produce intense highly charged ion beams for the application in heavy ion accelerators. Superconducting Electron Resonance ion source with Advanced Design (SECRAL) is one of the few fully superconducting ECR ion sources that has been successfully built and put into routine operation for years. With enormous efforts and R&D work, promising results have been achieved with the ion source. Heated by the microwave power from a 7 kW/24 GHz gyrotron microwave generator, very intense highly charged gaseous ion beams have been produced, such as 455 eµA Xe(27+), 236 eµA Xe(30+), and 64 eµA Xe(35+). Since heavy metallic ion beams are being more and more attractive and important for many accelerator projects globally, intensive studies have been made to produce highly charged heavy metal ion beams, such as those from bismuth and uranium. Recently, 420 eµA Bi(30+) and 202 eµA U(33+) have been produced with SECRAL source. This paper will present the latest results with SECRAL, and the operation status will be discussed as well. An introduction of recently started SECRAL II project will also be given in the presentation.

Anticancer therapy and apoptosis imaging.

Early response prediction is considered an essential tool to obtain a more customized anticancer treatment because it allows for the identification of patients who will benefit most from a particular therapy and prevents the exposure of those patients to toxic, non-effective regimens. Recent discoveries of novel markers in functional imaging have created exciting opportunities for in vivo visualization and quantification of cell death. This review will focus on in vivo apoptosis imaging with various radiotracers as predictive tools for tumor response after anticancer therapy. Particular focus will be on annexin V imaging, a technique with the largest clinical experience to date. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation.

BACKGROUND AND PURPOSE: Sensory neuronal and epidermal transient receptor potential ion channels (TRPs) serve an important role as pain sensor molecules. While many natural and synthetic ligands for sensory TRPs have been identified, little is known about the endogenous activator for TRPV4. Recently, we reported that endogenous metabolites produced by the mevalonate pathway regulate the activities of sensory neuronal TRPs. Here, we show that dimethylallyl pyrophosphate (DMAPP), a substance produced by the same pathway is an activator of TRPV4. EXPERIMENTAL APPROACH: We examined the effects of DMAPP on sensory TRPs using Ca²âº imaging and whole-cell electrophysiology experiments with a heterologous expression system (HEK293T cells transfected with individual TRP channels), cultured sensory neurons and keratinocytes. We then evaluated nociceptive behavioural and inflammatory changes upon DMAPP administration in mice in vivo. KEY RESULTS: In the HEK cell heterologous expression system, cultured sensory neurons and keratinocytes, µM concentrations of DMAPP activated TRPV4. Agonistic and antagonistic potencies of DMAPP for other sensory TRP channels were examined and activation of TRPV3 by camphor was found to be inhibited by DMAPP. In vivo assays, intraplantar injection of DMAPP acutely elicited nociceptive flinches that were prevented by pretreatment with TRPV4 blockers, indicating that DMAPP is a novel pain-producing molecule through TRPV4 activation. Further, DMAPP induced acute inflammation and noxious mechanical hypersensitivities in a TRPV4-dependent manner. CONCLUSIONS AND IMPLICATIONS: Overall, we found a novel sensory TRP acting metabolite and suggest that its use may help to elucidate the physiological role of TRPV4 in nociception and associated inflammation.

17(R)-resolvin D1 specifically inhibits transient receptor potential ion channel vanilloid 3 leading to peripheral antinociception.

BACKGROUND AND PURPOSE: Transient receptor potential ion channel vanilloid 3 (TRPV3) is expressed in skin keratinocytes and plays an important role in thermal and chemical nociceptions in the periphery. The presence of TRPV3 inhibitors would improve our understanding of TRPV3 function and help to develop receptor-specific analgesics. However, little is known about physiological substances that specifically inhibit TRPV3 activity. Here, we investigated whether 17(R)-resolvin D1 (17R-RvD1), a naturally occurring pro-resolving lipid specifically affects TRPV3 activity. EXPERIMENTAL APPROACH: We examined the effect of 17R-RvD1 on sensory TRP channels using Ca(2+) imaging and whole cell electrophysiology experiments in a HEK cell heterologous expression system, cultured sensory neurons and keratinocytes. We also examined changes in sensory TRP agonist-specific acute licking/flicking or flinching behaviours and mechanical and thermal pain behaviours using Hargreaves, Randall-Selitto and von Frey assay systems in the absence and presence of inflammation. KEY RESULTS: We showed that 17R-RvD1 specifically suppresses TRPV3-mediated activity at nanomolar and micromolar concentrations. The voltage-dependence of TRPV3 activation by camphor was shifted rightwards by 17R-RvD1, which indicates its inhibitory mechanism is as a result of a shift in voltage-dependence. Consistently, TRPV3-specific acute pain behaviours were attenuated by locally injected 17R-RvD1. Moreover, the administration of 17R-RvD1 significantly reversed the thermal hypersensitivity that occurs during an inflammatory response. Knockdown of epidermal TRPV3 blunted these antinociceptive effects of 17R-RvD1. CONCLUSIONS AND IMPLICATIONS: 17R-RvD1 is a novel natural inhibitory substance specific for TRPV3. The results of our behavioural studies suggest that 17R-RvD1 has acute analgesic potential via TRPV3-specific mechanisms.

A novel monoclonal antibody against human CD80 and its immune protection in a mouse lupus-like disease.

Blockade of the interactions between CD28/CTLA-4 and their ligands, CD80 (B7, B7.1)/CD86 (B70, B7.2), is an attractive means to induce antigen-specific peripheral tolerance in autoimmune disease and organ transplantation. In this study, we generated and characterized a monoclonal antibody (Clone 4E5) against human CD80. 4E5 could recognize both human and mouse CD80 and suppress mixed lymphocyte reaction in vitro. To investigate their potency for clinical use, we further administrated 4E5 to a mouse lupus-like disease model (C57BL/J6) induced by Pristane. 4E5 could inhibit the immune response and attenuate the severity of lupus-like disease. The data showed 4E5 function and suggested that blockade of CD80/CD28 co-stimulatory signal pathway with 4E5 is a promising strategy to decelerate the progression of lupus-like disease and other autoimmune diseases.

Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception.

BACKGROUND AND PURPOSE: Temperature-sensitive transient receptor potential ion channels (thermoTRPs) expressed in primary sensory neurons and skin keratinocytes play a crucial role as peripheral pain detectors. Many natural and synthetic ligands have been found to act on thermoTRPs, but little is known about endogenous compounds that inhibit these TRPs. Here, we asked whether resolvin D1 (RvD1), a naturally occurring anti-inflammatory and pro-resolving lipid molecule is able to affect the TRP channel activation. EXPERIMENTAL APPROACH: We examined the effect of RvD1 on the six thermoTRPs using Ca(2+) imaging and whole cell electrophysiology experiments using the HEK cell heterologous expression system, cultured sensory neurons and HaCaT keratinocytes. We also checked changes in agonist-specific acute licking/flicking or flinching behaviours and TRP-related mechanical and thermal pain behaviours using Hargreaves, Randall-Selitto and von Frey assay systems with or without inflammation. KEY RESULTS: RvD1 inhibited the activities of TRPA1, TRPV3 and TRPV4 at nanomolar and micromolar levels. Consistent attenuations in agonist-specific acute pain behaviours by immediate peripheral administration with RvD1 were also observed. Furthermore, local pretreatment with RvD1 significantly reversed mechanical and thermal hypersensitivity in inflamed tissues. CONCLUSIONS AND IMPLICATIONS: RvD1 was a novel endogenous inhibitor for several sensory TRPs. The results of our behavioural studies suggest that RvD1 has an analgesic potential via these TRP-related mechanisms.

Laser modulation of heat and capsaicin receptor TRPV1 leads to thermal antinociception.

Er,Cr:YSGG lasers are used clinically in dentistry. The advantages of laser therapy include minimal thermal damage and the alleviation of pain. This study examined whether the Er,Cr:YSGG laser has in vivo and in vitro antinociceptive effects in itself. In capsaicin-evoked acute licking/shaking tests and Hargreaves tests, laser irradiation with an aerated water spray suppressed nociceptive behavior in mice. Laser irradiation attenuated TRPV1 activation by capsaicin in Ca(2+) imaging experiments with TRPV1-overexpressing cells and cultured trigeminal neurons. Therefore, the laser-induced behavioral changes are probably due to the loss of TRPV1 activity. TRPV4 activity was also attenuated, but limited mechanical antinociception by the laser was observed. The laser failed to alter the other receptor functions, which indicates that the antinociceptive effect of the laser is dependent on TRPV1. These results suggest that the Er,Cr:YSGG laser has analgesic effects via TRPV1 inhibition. Such mechanistic approaches may help define the laser-sensitive pain modality and increase its beneficial uses.